PubMedHealth PMH0041115

Ovarian cancer:
the recognition and initial

management of ovarian cancer
This guidance updates and replaces recommendation 1.7.4 in

Referral guidelines for suspected cancer (NICE clinical guideline
27; published June 2005).
Full Guideline
April 2011
Developed for NICE by the National Collaborating Centre for Cancer
Published by the National Collaborating Centre for Cancer (2nd Floor, Front Suite, Park House, Greyfriars Road, Cardiff,
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First published 2011
2011 National Collaborating Centre for Cancer
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Contents
Foreword
iv
Key priorities
Key research recommendations
vii
List of all recommendations
ix
Methodology
xiii
Algorithms
xxiii
1
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
Epidemiology
Introduction
Data collection
Incidence
Mortality
Survival
Routes to diagnosis
Treatment
The findings of cancer peer review of gynaecology cancer teams in England 2004-2007
Summary
1
1
1
2
5
9
12
12
13
14
2
2.1
2.2
Detection in primary care

Awareness of symptoms and signs
Asking the right question - first tests
16
16
21
Establishing the diagnosis in secondary care
28
3.1
Tumour markers: which to use?
28
3.2
Malignancy indices
30
3.3
Imaging in the diagnostic pathway: which procedures?
32
3.4
Tissue diagnosis
34
Management of suspected early (stage I) ovarian cancer
40
4.1
The role of systematic retroperitoneal lymphadenectomy
40
4.2
Adjuvant systemic chemotherapy for stage I disease
46
Management of advanced (stage II-IV) ovarian cancer
55
5.1
The value of primary surgery
55
5.2
Intraperitoneal chemotherapy
61
5.3
Chemotherapy regimens
69
Support needs of women with newly diagnosed ovarian cancer
72
1
2
3
4
5
6
Appendices
A cost-utility analysis of diagnostic investigations in primary care for women with symptoms of ovarian
cancer
Abbreviations
Glossary
Guideline scope
List of topics covered by each chapter
People and organisations involved in production of the guideline
NHS Evidence has accredited the process used by the National Collaborating
Centre for Cancer to produce guidelines. Accreditation is valid for three years from
January 2009 and is applicable to guidance produced using the processes described
in The guidelines manual, NICE 2009. More information on accreditation can be viewed
at www.evidence.nhs.uk
75
97
98
107
111
112
Foreword
These clinical guidelines review a number of clinical questions that involve the detection,
diagnosis and initial management of ovarian cancer and which focus on areas of
uncertainty or where there is a wide variation in clinical practice.
The clinical questions were chosen using a consultative process that involved an array of
stakeholders that included patient groups, representatives from relevant professional
organisations and the pharmaceutical industry.
For each chapter of the guideline, the Guideline Development Group (GDG) have made
evidence-based recommendations concerning clinical practice and, where applicable,
some recommendations on future research.
The GDG are pleased that the focus of many of the clinical issues relate to an early stage in
the patient pathway with particular relevance to patients and their families. In particular,
identifying the first tests in primary care should help ensure women are directed onto the
right clinical pathway in a timely fashion.
The chair and lead clinician were aided and supported by a diverse and engaged GDG
membership whose complementary skills and perspectives have been instilled in this
guideline.
Mr Sean Duffy
GDG Chair
iv
Mr Charles Redman
GDG Lead clinician
Key priorities

1. Carry out tests in primary care (see section 2.2 on page 21) if a woman (especially if 50
or over) reports having any of the following symptoms on a persistent or frequent basis
particularly more than 12 times per month1:
persistent abdominal distension (women often refer to this as bloating)
feeling full (early satiety) and/or loss of appetite
pelvic or abdominal pain
increased urinary urgency and/or frequency.
2. Carry out appropriate tests for ovarian cancer (see section 2.2. on page 21) in any
woman of 50 or over who has experienced symptoms within the last 12 months that
suggest irritable bowel syndrome (IBS)2, because IBS rarely presents for the first time in
women of this age.
Asking the right question first tests

3. Measure serum CA125 in primary care in women with symptoms that suggest ovarian
cancer (see section 2.1 on page 16).
4. If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and
pelvis.
5. For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35
IU/ml or greater but a normal ultrasound:
assess her carefully for other clinical causes of her symptoms and investigate if
appropriate
if no other clinical cause is apparent, advise her to return to her GP if her
symptoms become more frequent and/or persistent.
Malignancy indices
6. Calculate a risk of malignancy index I (RMI I) score3 (after performing an ultrasound;
see section 3.3 on page 32) and refer all women with an RMI I score of 250 or greater
to a specialist multidisciplinary team.
Tissue diagnosis
7. If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer,
first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not
appropriate) in all but exceptional cases.
1
See also Referral guidelines for suspected cancer (NICE clinical guideline 27; available at www.nice.org.uk/guidance/CG27) for
recommendations about the support and information needs of people with suspected cancer.
2
See Irritable bowel syndrome in adults (NICE clinical guideline 61; available at www.nice.org.uk/guidance/CG61).
See Box 3.1 for details of how to calculate an RMI I score.
Ovarian cancer: the recognition and initial management of ovarian cancer

8. Do not include systematic retroperitoneal lymphadenectomy (block dissection of
lymph nodes from the pelvic side walls to the level of the renal veins) as part of
standard surgical treatment in women with suspected ovarian cancer whose disease
appears to be confined to the ovaries (that is, who appear to have stage I disease).

9. Do not offer adjuvant chemotherapy to women who have had optimal surgical staging4
and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).
Support needs of women with newly diagnosed ovarian cancer

10. Offer all women with newly diagnosed ovarian cancer information about their disease,
including psychosocial and psychosexual issues, that:
is available at the time they want it
includes the amount of detail that they want and are able to deal with
is in a suitable format, including written information.
4
Optimal surgical staging constitutes midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total
abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits;
random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment [Winter Roach BA,
Kitchener HC, Dickinson HO (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane
Database of Systematic Reviews, Issue 3: CD004706]
vi
Key research
recommendations
1. Further research should be undertaken on the relationship between the duration and
frequency of symptoms in women with ovarian cancer before diagnosis, the stage of
disease at diagnosis and subsequent survival.
Most women presenting with ovarian cancer have advanced disease and have had
symptoms for months. Greater awareness among both women and healthcare
professionals might result in women presenting earlier with less advanced disease,
leading to better outcomes. There is insufficient understanding of the factors that
influence earlier diagnosis in women with ovarian cancer, especially the relationship
between duration of symptoms and stage at diagnosis. Data demonstrating benefits from
earlier presentation will justify investment in raising awareness among women and
healthcare professionals. This is likely to be a population-based study that records both
the duration and frequency of symptoms.
2. Further research should be undertaken to determine the optimum RMI I threshold that
should be applied in secondary care to guide the management of women with
suspected ovarian cancer.
Variation exists in the current evidence base with regard to the optimum RMI I threshold
that should be applied in secondary care. The cut-off levels used will have implications
for both the management options considered and the number of women who will be
referred for specialist treatment. Therefore it is important to establish the relative
sensitivities and specificities at the different levels. The research should be a prospective
observational cohort study evaluating women referred with suspected ovarian cancer.
Diagnostic accuracy, sensitivity, specificity and cost effectiveness should be examined
at the different RMI I thresholds.
3. Large multicentre casecontrol studies should be conducted to compare the accuracy
of CT versus MRI for staging and for predicting optimal cytoreduction in women with
ovarian cancer.
Currently most women with ovarian cancer will undergo a CT scan before surgery to
assess the extent and resectability of disease. CT and MRI are complementary in their
abilities to detect disease, but no adequate studies have been performed that compare
their effectiveness in women with suspected ovarian cancer. No comparative studies
have been undertaken evaluating surgical outcome. A prospective study in women
undergoing primary surgery would be feasible.
4. A prospective randomised trial should be undertaken to evaluate the therapeutic
effect, associated risks and cost effectiveness of systematic retroperitoneal
lymphadenectomy in women with ovarian cancer whose disease appears to be
confined to the ovaries.
vii
Systematic retroperitoneal lymphadenectomy is an untested procedure but is likely to be

more accurate than lymph node sampling, with a potential benefit for the woman of
avoiding chemotherapy. However, increased risks are associated with it. Although there
may be no overall survival advantage of this procedure, avoidance of chemotherapy
and impact on quality of life may make it attractive to some women as a treatment
option. In order to counsel women appropriately it is essential to understand fully the
risks associated with this surgery as well as the benefits. Researchers should be
encouraged to develop a prospective randomised trial with international collaboration
to answer this question in a timely manner.
5. Research should be undertaken to determine the effectiveness of primary surgery for
women with advanced ovarian cancer whose tumour cannot be fully excised.
Most women with advanced ovarian cancer undergo surgery at some point. Previous
studies have shown that surgery after the completion of chemotherapy has no
therapeutic value. Studies are being performed to investigate whether the timing of
surgery during primary chemotherapy influences outcome. No studies have evaluated
whether primary surgery itself has any therapeutic value when compared with
chemotherapy alone. The potential advantages of surgery have to be offset against the
morbidity, occasional mortality and undoubted costs associated with it. This would be a
prospective randomised clinical trial recruiting women who have biopsy-proven
advanced ovarian cancer and who are fit enough to receive surgery and chemotherapy.
Women would be randomised to either chemotherapy and surgery (conventional arm)
or chemotherapy alone (experimental arm). Primary outcome measures would be
survival at 1 and 5 years.
viii
Chapter 2: Detection in primary care

Refer the woman urgently1 if physical examination identifies ascites and/or a pelvic or
abdominal mass (which is not obviously uterine fibroids)2.
Carry out tests in primary care (see section 2.2 on page 21) if a woman (especially if 50
or over) reports having any of the following symptoms on a persistent or frequent basis
particularly more than 12 times per month2:
Consider carrying out tests in primary care (see section 2.2 on page 21) if a woman
reports unexplained weight loss, fatigue or changes in bowel habit.
Advise any woman who is not suspected of having ovarian cancer to return to her GP if
her symptoms become more frequent and/or persistent.
Carry out appropriate tests for ovarian cancer (see section 2.2 on page 21) in any
woman of 50 or over who has experienced symptoms within the last 12 months that
suggest irritable bowel syndrome (IBS)3, because IBS rarely presents for the first time in
women of this age.
Measure serum CA125 in primary care in women with symptoms that suggest ovarian
cancer (see section 2.1 on page 16).
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and
pelvis.
If the ultrasound suggests ovarian cancer, refer the woman urgently1 for further
investigation2.
For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35
IU/ml or greater but a normal ultrasound:
assess her carefully for other clinical causes of her symptoms and investigate if
appropriate
An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and
Wales for referral for suspected cancer, which is currently 2 weeks.
2
3
See Irritable bowel syndrome in adults (NICE clinical guideline 61; available at www.nice.org.uk/guidance/CG61).
ix
Chapter 3: Establishing the diagnosis in secondary care

Measure serum CA125 in secondary care in all women with suspected ovarian cancer,
if this has not already been done in primary care.
In women under 40 with suspected ovarian cancer, measure levels of alpha fetoprotein
(AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as serum CA125, to
identify women who may not have epithelial ovarian cancer.
Malignancy indices
Calculate a risk of malignancy index I (RMI I) score4 (after performing an ultrasound;

see section 3.3 on page 32) and refer all women with an RMI I score of 250 or greater
to a specialist multidisciplinary team.
Perform an ultrasound of the abdomen and pelvis as the first imaging test in secondary
care for women with suspected ovarian cancer, if this has not already been done in
primary care.
If the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a
CT scan of the pelvis and abdomen to establish the extent of disease. Include the
thorax if clinically indicated.
Do not use MRI routinely for assessing women with suspected ovarian cancer.
Tissue diagnosis
Requirement for tissue diagnosis
If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer,

first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not
appropriate) in all but exceptional cases.
Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without a tissue
diagnosis (histology or cytology) only:
in exceptional cases, after discussion at the multidisciplinary team and
after discussing with the woman the possible benefits and risks of starting
chemotherapy without a tissue diagnosis.
Methods of tissue diagnosis other than laparotomy
If surgery has not been performed, use histology rather than cytology to obtain a
diagnosis. To obtain tissue for histology:
use percutaneous image-guided biopsy if this is feasible
consider laparoscopic biopsy if percutaneous image-guided biopsy is not feasible
or has not produced an adequate sample.
Use cytology if histology is not appropriate.
Chapter 4: Management of suspected early (stage I)

ovarian cancer
Perform retroperitoneal lymph node assessment5 as part of optimal surgical staging6 in

women with suspected ovarian cancer whose disease appears to be confined to the
ovaries (that is, who appear to have stage I disease).
Do not include systematic retroperitoneal lymphadenectomy (block dissection of
lymph nodes from the pelvic side walls to the level of the renal veins) as part of
standard surgical treatment in women with suspected ovarian cancer whose disease
appears to be confined to the ovaries (that is, who appear to have stage I disease).
Do not offer adjuvant chemotherapy to women who have had optimal surgical staging6
and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).
Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy
consisting of six cycles of carboplatin.
Discuss the possible benefits and side effects of adjuvant chemotherapy with women
who have had suboptimal surgical staging6 and appear to have stage I disease.
Chapter 5: Management of advanced (stage IIIV)

ovarian cancer
Primary surgery
If performing surgery for women with ovarian cancer, whether before chemotherapy or
after neoadjuvant chemotherapy, the objective should be complete resection of all
macroscopic disease.
Do not offer intraperitoneal chemotherapy to women with ovarian cancer, except as

part of a clinical trial.
Chapter 6: Support needs of women with newly diagnosed

ovarian cancer
Offer all women with newly diagnosed ovarian cancer information about their disease,
including psychosocial and psychosexual issues, that:
Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if
there is a palpable abnormality, or random sampling if there is no palpable abnormality.
6
Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total
random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment [Winter Roach BA,
Database of Systematic Reviews issue 3: CD004706].
xi
xii
Ensure that information is available about:

the stage of the disease, treatment options and prognosis
how to manage the side effects of both the disease and its treatments in order to
maximise wellbeing
sexuality and sexual activity
fertility and hormone treatment
symptoms and signs of disease recurrence
genetics, including the chances of family members developing ovarian cancer
self-help strategies to optimise independence and coping
where to go for support, including support groups
how to deal with emotions such as sadness, depression, anxiety and a feeling of a
lack of control over the outcome of the disease and treatment.
Methodology
Introduction
What is a clinical guideline?
Guidelines are recommendations for the care of individuals in specific clinical conditions
or circumstances from prevention and self-care through to primary and secondary care
and on to more specialised services. NICE clinical guidelines are based on the best
available evidence of clinical and cost effectiveness, and are produced to help healthcare
professionals and patients make informed choices about appropriate healthcare. While
guidelines assist the practice of healthcare professionals, they do not replace their
knowledge and skills.
Clinical guidelines for the NHS in England, Wales and Northern Ireland are produced as a
response to a request from the Department of Health (DH). They approve topics for
guideline development. Before deciding whether to refer a particular topic to the National
Institute for Health and Clinical Excellence (NICE) they consult with the relevant patient
bodies, professional organisations and companies. Once a topic is referred, NICE then
commissions one of four National Collaborating Centres (NCCs) to produce a guideline.
The Collaborating Centres are independent of government and comprise partnerships
between a variety of academic institutions, health profession bodies and patient groups.
The National Collaborating Centre for Cancer (NCC-C) was referred the topic of the
recognition and initial management of ovarian cancer in October 2007 as part of NICEs
seventeenth wave work programme. However, the guideline development process began
officially in February 2009 when sufficient capacity became available at the NCC-C.
Who is the guideline intended For?

This guideline does not include recommendations covering every detail of the recognition
and initial management of ovarian cancer. Instead this guideline has tried to focus on those
areas of clinical practice (i) that are known to be controversial or uncertain; (ii) where there
is identifiable practice variation; (iii) where there is a lack of high quality evidence; or (iv)
where NICE guidelines are likely to have most impact. More detail on how this was
achieved is presented later in the section on Developing Clinical Evidence Based
Questions.
This guideline is relevant to all healthcare professionals who come into contact with
patients with ovarian cancer or suspected of having ovarian cancer, as well as to the
patients themselves and their carers. It is also expected that the guideline will be of value to
those involved in clinical governance in both primary and secondary care to help ensure
that arrangements are in place to deliver appropriate care for the population covered by
this guideline.
The remit of the guideline

Guideline topics selected by the DH identify the main areas to be covered by the guideline
in a specific remit. The following remit for this guideline was received as part of NICEs
seventeenth wave programme of work:
To prepare a clinical guideline on the recognition and initial management of ovarian
cancer, to include both surgery and chemotherapy.
xiii
Involvement of stakeholders
Key to the development of all NICE guidance is the involvement of relevant professional
and patient/carer organisations that register as stakeholders. Details of this process can be
found on the NICE website or in the NICE guidelines manual (NICE 2009). In brief, their
contribution involves commenting on the draft scope, submitting relevant evidence and
commenting on the draft version of the guideline during the end consultation period. A full
list of all stakeholder organisations who registered for the recognition and initial
management of ovarian cancer guideline can be found in Appendix 6.2.
The process of guideline development who develops the

guideline?
Overview
The development of this guideline was based upon methods outlined in the NICE
guidelines manual (NICE 2009). A team of health professionals, lay representatives and
technical experts known as the Guideline Development Group (GDG) (see Appendix 6.1),
with support from the NCC-C staff, undertook the development of this clinical guideline.
The basic steps in the process of developing a guideline are listed and discussed below:
using the remit, define the scope which sets the inclusion/exclusion critera of the
guideline
forming the GDG
developing clinical questions
developing the review protocol
systematically searching for the evidence
critically appraising the evidence
incorporating health economic evidence
distilling and synthesising the evidence and writing recommendations
agreeing the recommendations
structuring and writing the guideline
updating the guideline.
The scope
The remit was translated into a scope document by the Guideline Development Group
(GDG) Chair and Lead Clinician and staff at the NCC-C in accordance with processes
established by NICE (NICE 2009). The purpose of the scope was to:
set the boundaries of the development work and provide a clear framework to enable
work to stay within the priorities agreed by NICE and the NCC-C and the remit set by
the DH
inform professionals and the public about the expected content of the guideline.
provide an overview of the population and healthcare settings the guideline would
include and exclude
specify the key clinical issues that will be covered by the guideline
inform the development of the clinical questions and search strategy
Before the guideline development process started, the draft scope was presented and
discussed at a stakeholder workshop. The list of key clinical issues were discussed and
revised before the formal consultation process. Further details of the discussion at the
stakeholder
workshop
can
be
found
on
the
NICE
website
(http://www.nice.org.uk/guidance/index.jsp?action=folder&o=46933).
The scope was subject to a four week stakeholder consultation in accordance with
processes established by NICE in the NICE guidelines manual (NICE 2009). The full scope
is shown in Appendix 4. During the consultation period, the scope was posted on the NICE
website (www.nice.org.uk). Comments were invited from registered stakeholder
xiv
Methodology
organisations and the NICE Guideline Review Panel (GRP). Further information about the
GRP can also be found on the NICE website. The NCC-C and NICE reviewed the scope in
light of comments received, and the revised scope was reviewed by the GRP, signed off by
NICE and posted on the NICE website.
The guideline development group (GDG)

The ovarian cancer GDG was recruited in line with the NICE guidelines manual (NICE
2009). The first step was to appoint a Chair and a Lead Clinician. Advertisements were
placed for both posts and candidates were interviewed before being offered the role. The
NCC-C Director, GDG Chair and Lead Clinician identified a list of specialties that needed
to be represented on the GDG. Requests for applications were sent to the main stakeholder
organisations, cancer networks and patient organisations/charities (see Appendix 6.2).
Individual GDG members were selected by the NCC-C Director, GDG Chair and Lead
Clinician, based on their application forms. The guideline development process was
supported by staff from the NCC-C, who undertook the clinical and health economics
literature searches, reviewed and presented the evidence to the GDG, managed the process
and contributed to drafting the guideline. At the start of the guideline development process
all GDG members interests were recorded on a standard declaration form that covered
consultancies, fee-paid work, share-holdings, fellowships and support from the healthcare
industry. At all subsequent GDG meetings, members declared new, arising conflicts of
interest which were always recorded (see Appendix 6.1).
Guideline Development Group meetings

Eleven GDG meetings were held between 27 April 2009 and 20 July 2010. During each
GDG meeting (either held over one or two days) clinical questions and clinical and
economic evidence were reviewed, assessed and recommendations formulated. At each
meeting patient/carer and service-user concerns were routinely discussed as part of a
standing agenda item.
NCC-C project managers divided the GDG workload by allocating specific clinical
questions, relevant to their area of clinical practice, to small sub-groups of the GDG in
order to simplify and speed up the guideline development process. These groups
considered the evidence, as reviewed by the researcher, and synthesised it into draft
recommendations before presenting it to the GDG as a whole. Each clinical question was
led by a GDG member with expert knowledge of the clinical area (usually one of the
healthcare professionals). The GDG subgroups often helped refine the clinical questions
and the clinical definitions of treatments. They also assisted the NCC-C team in drafting the
section of the guideline relevant to their specific topic.
Patient/carer members
Individuals with direct experience of ovarian cancer gave an important user focus to the
GDG and the guideline development process. The GDG included three patient/carer
members. They contributed as full GDG members to writing the clinical questions, helping
to ensure that the evidence addressed their views and preferences, highlighting sensitive
issues and terminology relevant to the guideline and bringing service-user research to the
attention of the GDG.
Developing Clinical Evidence-Based Questions

Background
Clinical guidelines should be aimed at improving clinical practice and should avoid ending
up as evidence-based textbooks or making recommendations on topics where there is
already agreed clinical practice. Therefore the list of key clinical issues listed in the scope
were developed in areas that were known to be controversial or uncertain, where there was
identifiable practice variation, or where NICE guidelines were likely to have most impact.
xv
Method
From each of the key clinical issues identified in the scope the GDG formulated a clinical
question. For clinical questions about interventions, the PICO framework was used. This
structured approach divides each question into four components: the population (the
population under study P), the interventions (what is being done - I), the comparisons
(other main treatment options C) and the outcomes (the measures of how effective the
interventions have been O). Where appropriate, the clinical questions were refined once
the evidence had been searched and, where necessary, sub-questions were generated.
The final list of clinical questions can be found in Appendix 5.
Review of Clinical Literature

Scoping search
An initial scoping search for published guidelines, systematic reviews, economic
evaluations and ongoing research was carried out on the following databases or websites:
National Library for Health (NLH) Guidelines Finder (now NHS Evidence), National
Guidelines Clearinghouse, Cochrane Database of Systematic Reviews (CDSR), Heath
Technology Assessment Database (HTA), NHS Economic Evaluations Database (NHSEED),
DH Data, Medline and Embase.
At the beginning of the development phase, initial scoping searches were carried out to
identify any relevant guidelines (local, national or international) produced by other groups
or institutions.
Developing the review protocol

For each clinical question, the information specialist and researcher (with input from other
technical team and GDG members) prepared a review protocol. This protocol explains
how the review was to be carried out (see Table A) in order to develop a plan of how to
review the evidence, limit the introduction of bias and for the purposes of reproducibility.
All review protocols can be in the full evidence review.
Table A Components of the review protocol
xvi
Component
Description
Clinical question
The clinical question as agreed by the GDG.
Objectives
Short description; for example To estimate the effects and

cost effectiveness of or To estimate the diagnostic
accuracy of.
Criteria for considering studies for the review
Using the PICO (population, intervention, comparison

and outcome) framework. Including the study designs
selected.
How the information will be searched
The sources to be searched and any limits that will be

applied to the search strategies; for example, publication
date, study design, language. (Searches should not
necessarily be restricted to RCTs.)
The review strategy
The methods that will be used to review the evidence,

outlining exceptions and subgroups. Indicate if metaanalysis will be used.
Methodology
Searching for the evidence

In order to answer each question the NCC-C information specialist developed a search
strategy to identify relevant published evidence for both clinical and cost effectiveness. Key
words and terms for the search were agreed in collaboration with the GDG. When
required, the health economist searched for supplementary papers to inform detailed health
economic work (see section on Incorporating Health Economic Evidence).
Search filters, such as those to identify systematic reviews (SRs) and randomised controlled
trials (RCTs) were applied to the search strategies when there was a wealth of these types of
studies. No language restrictions were applied to the search; however, foreign language
papers were not requested or reviewed (unless of particular importance to that question).
The following databases were included in the literature search:
The Cochrane Library
Medline and Premedline 1950 onwards
Excerpta Medica (Embase) 1980 onwards
Cumulative Index to Nursing and Allied Health Literature (Cinahl) 1982 onwards
Allied & Complementary Medicine (AMED) 1985 onwards
British Nursing Index (BNI) 1985 onwards
Psychinfo 1806 onwards
Web of Science [specifically Science Citation Index Expanded]
(SCI-EXPANDED) 1899 onwards and Social Sciences Citation Index (SSCI) 1956
onwards
Biomed Central 1997 onwards
From this list the information specialist sifted and removed any irrelevant material based on
the title or abstract before passing to the researcher. All the remaining articles were then
stored in a Reference Manager electronic library.
Searches were updated and re-run 68 weeks before the stakeholder consultation, thereby
ensuring that the latest relevant published evidence was included in the database. Any
evidence published after this date was not included. For the purposes of updating this
guideline, 16 July 2010 should be considered the starting point for searching for new
evidence.
Further details of the search strategies, including the methodological filters used, are
provided in the evidence review (and appear on the CD-ROM accompanying this
guideline).
Critical Appraisal
From the literature search results database, one researcher scanned the titles and abstracts
of every article for each question and full publications were ordered for any studies
considered relevant or if there was insufficient information from the title and abstract to
inform a decision. When the papers were obtained the researcher applied
inclusion/exclusion criteria to select appropriate studies which were then critically
appraised. For each question, data on the type of population, intervention, comparator and
outcomes (PICO) were extracted and recorded in evidence tables and an accompanying
evidence summary prepared for the GDG (see evidence review). All evidence was
considered carefully by the GDG for accuracy and completeness.
GRADE (Grading of Recommendations, Assessment, Development and

Evaluation)
For interventional questions, studies which matched the inclusion criteria were evaluated
and presented using a modification of GRADE (NICE 2009; http://gradeworking group.org/).
Where possible this included meta-analysis and synthesis of data into a GRADE evidence
profile. The evidence profile shows, for each outcome, an overall assessment of both the
quality of the evidence as a whole (low, moderate or high) as well as an estimate of the size
of effect. A narrative summary (evidence statement) was also prepared.
xvii
Each topic outcome was examined for the quality elements defined in table B and
subsequently graded using the quality levels listed in table C. The reasons for downgrading
or upgrading specific outcomes were explained in footnotes.
Table B Descriptions of quality elements of GRADE
Quality element
Description
Limitations
Limitations in the study design and implementation may bias the estimates of the
treatment effect. Major limitations in studies decrease the confidence in the
estimate of the effect.
Inconsistency
Inconsistency refers to an unexplained heterogeneity of results.
Indirectness
Indirectness refers to differences in study population, intervention, comparator or

outcomes between the available evidence and the clinical question.
Imprecision
Results are imprecise when studies include relatively few patients and few events
and thus have wide confidence intervals around the estimate of the effect relative
to the minimal important difference.
Publication bias
Publication bias is a systematic underestimate or overestimate of the underlying

beneficial or harmful effect due to the selective publication of studies.
Table C Overall quality of outcome evidence in GRADE

Quality element
Description
High
Further research is very unlikely to change our confidence in the estimate of effect.
Moderate
Further research is likely to have an important impact on our confidence in the

estimate of effect and may change the estimate.
Low
Further research is very likely to have an important impact on our confidence in

the estimate of effect and is likely to change the estimate.
Very low
Any estimate of effect is very uncertain.
All procedures were fully compliant with NICE methodology as detailed in the NICE
guidelines manual (NICE 2009). In general, no formal contact was made with authors;
however, there were ad hoc occasions when this was required in order to clarify specific
details.
Needs assessment
As part of the guideline development process the NCC-C invited a specialist registrar, with
the support of the GDG, to undertake a needs assessment (see Appendix 6.3). The needs
assessment aims to describe the burden of disease and current service provision for patients
with ovarian cancer in England and Wales, which informed the development of the
guideline.
Assessment of the effectiveness of interventions is not included in the needs assessment,
and was undertaken separately by researchers in the NCC-C as part of the guideline
development process.
The information included in the needs assessment document was presented to the GDG.
Most of the information was presented in the early stages of guideline development, and
other information was included to meet the evolving information needs of the GDG during
the course of guideline development.
xviii
Methodology
Incorporating Health Economics Evidence

The aim of providing economic input into the development of the guideline was to inform
the GDG of potential economic issues relating to the recognition and initial management of
ovarian cancer. It is important to investigate whether health services are both clinically
effective and cost effective, i.e. are they value for money.
Prioritising topics for economic analysis

In addition to the review of the relevant clinical evidence, the GDG were required to
determine whether or not the cost-effectiveness of each of the individual clinical questions
should or could be investigated. After the clinical questions were decided, and with the
help of the health economist, the GDG agreed which of the clinical questions were an
economic priority for analysis. Further details of the economic prioritisation are provided in
the evidence review (and appear on the CD-ROM accompanying this guideline). These
economic priorities were chosen on the basis of the following criteria, in broad
accordance with the NICE guidelines manual (NICE 2009):
Overall relevance of the topic:
The number of patients affected: interventions affecting relatively large numbers of
patients were given a higher economic priority than those affecting fewer patients
The health benefits to the patient: interventions that were considered to have a
potentially significant impact on both survival and quality of life were given a higher
economic priority
The per patient cost: interventions with potentially high financial (cost/savings)
implications were given high priority compared to interventions expected to have
lower financial implications
Likelihood of changing clinical practice: priority was given to topics that were
considered likely to represent a significant change to existing clinical practice.
Uncertainty:
High level of existing uncertainty: higher economic priority was given to clinical
questions in which further economic analysis was considered likely to reduce current
uncertainty over cost-effectiveness. Low priority was given to clinical questions when
the current literature implied a clearly attractive or unattractive incremental costeffectiveness ratio, which was regarded as generalisable to a UK healthcare setting
Likelihood of reducing uncertainty with further analyses (feasibility issues): when there
was poor evidence for the clinical effectiveness of an intervention, there was
considered to be less justification for an economic analysis to be undertaken.
For each topic that was prioritised for economic analysis a comprehensive systematic
review of the economic literature was conducted. Where published economic evaluation
studies were identified that addressed the economic issues for a clinical question, these are
presented alongside the clinical evidence wherever possible. For those clinical areas
reviewed, the information specialists used a similar search strategy as used for the review of
clinical evidence but with the inclusion of a health economics filter. Each search strategy
was designed to find any applied study estimating the cost or cost effectiveness of the topic
under consideration. A health economist reviewed abstracts and relevant papers were
ordered for appraisal.
Published economic evidence was obtained from a variety of sources:
Cochrane HTA
NHS Economic Evaluations Database (NHS EED)
Medline
Embase.
Economic analysis
Once the priority topics for economic analysis had been agreed by the GDG, the health
economist investigated whether or not a cost-effectiveness analysis of each topic could be
xix
carried out. Cost-effectiveness evaluations require evidence on numerous parameters,

including treatment effects, health-related preferences (utilities), healthcare resource use
and costs. However, high quality evidence on all relevant parameters within an economic
analysis is not always available. If the evidence base used to inform a cost-effectiveness
analysis is poor, decisions based upon such an analysis may be subject to a high degree of
uncertainty and therefore cost effectiveness analysis would not be appropriate.
For those clinical questions where an economic model was required, cost-utility analysis
was undertaken using a decision tree approach. Decision tree is an analytical method of
evaluating all options and consequences relevant to a specific decision problem.
Assumptions and designs of the decision models were explained to and agreed by the GDG
members during meetings, and they commented on subsequent revisions.
The details of the model are presented in the evidence review and Appendix 1. During the
analysis the following general principles were adhered to:
the GDG Chair and Clinical Lead were consulted during the construction and
interpretation of the analysis
the analysis was based on the best evidence from the systematic review
assumptions were reported fully and transparently
the results were subject to thorough sensitivity analysis and limitations discussed
costs were calculated from a health services perspective.
Linking to NICE technology appraisals

When this guideline was commissioned there was one published technology appraisal (TA)
which was relevant to the guideline (TA55: Paclitaxel for the treatment of ovarian cancer;
http://guidance.nice.org.uk/TA55). Published TAs are periodically reviewed to determine if
they need to be updated particularly if any new evidence becomes available since the
publication of the appraisal which means the original recommendations needed to be
changed. In October 2009, NICE consulted with stakeholders to assess whether TA55
should be updated within the guideline. The outcome was that TA55 should remain on the
static list and therefore its recommendations were reproduced unchanged in the most
appropriate section of the guideline
Agreeing the Recommendations

For each clinical question the GDG were presented with a summary of the clinical
evidence, and where appropriate economic evidence, derived from the studies reviewed
and appraised. From this information the GDG were able to derive the guideline
recommendations. The link between the evidence and the view of the GDG in making
each recommendation is made explicit in the accompanying LETR statement.
LETR (Linking Evidence to Recommendations) statements

As clinical guidelines were previously formatted, there was limited scope for expressing
how and why a GDG made a particular recommendation from the evidence of clinical and
cost effectiveness. To make this process more transparent to the reader, NICE have
introduced an explicit, easily understood and consistent way of expressing the reasons for
making each recommendation. This is known as the LETR statement and will usually
cover the following key points:
the relative value placed on the outcomes considered
the strength of evidence about benefits and harms for the intervention being considered
the costs and cost-effectiveness of an intervention (if formally assessed by the health
economics team)
the quality of the evidence (see GRADE)
the degree of consensus within the GDG
other considerations for example equalities issues
xx
Methodology
Where evidence was weak or lacking the GDG agreed the final recommendations through
informal consensus. Shortly before the consultation period, ten key priorities and five key
research recommendations were selected by the GDG for implementation and the patient
algorithms were agreed. To avoid giving the impression that higher grade recommendations
are of higher priority for implementation, NICE no longer assigns grades to
recommendations.
Consultation and Validation of the Guideline

The draft of the guideline was prepared by NCC-C staff in partnership with the GDG Chair
and Lead Clinician. This was then discussed and agreed with the GDG and subsequently
forwarded to NICE for consultation with stakeholders.
Registered stakeholders (see Appendix 6.2) had one opportunity to comment on the draft
guideline which was posted on the NICE website between 24 September 2010 and 19
November 2010 in line with NICE methodology (NICE 2009). The Guideline Review Panel
also reviewed the guideline and checked that stakeholder comments had been addressed.
The pre-publication check process

Following stakeholder consultation and subsequent revision, the draft guideline was then
subject to a pre-publication check (NICE 2009). The pre-publication check provides
registered stakeholders with the opportunity to raise any concerns about factual errors and
inaccuracies that may exist in the revised guideline after consultation.
During the pre-publication check the full guideline was posted on the NICE website for 15
working days, together with the guideline consultation table that listed comments received
during consultation from stakeholders and responses from the NCC-C and GDG.
All stakeholders were invited to report factual errors using a standard proforma. NICE, the
NCC and the GDG Chair and Lead Clinician considered the reported errors and responded
only to those related to factual errors. A list of all corrected errors and the revised guideline
were submitted to NICE, and the revised guideline was then signed off by Guidance
Executive. The list of reported errors from the pre-publication check and the responses from
the NCC-C were subsequently published on the NICE website.
The final document was then submitted to NICE for publication on their website. The other
versions of the guideline (see below) were also discussed and approved by the GDG and
published at the same time.
Other Versions of the Guideline

This full version of the guideline is available to download free of charge from the NICE
website (www.nice.org.uk) and the NCC-C website (www.wales.nhs.uk/nccc).
NICE also produces three other versions of the ovarian cancer guideline which are
available from the NICE website:
the NICE guideline, which is a shorter version of this guideline, containing the key
priorities, key research recommendations and all other recommendations
the Quick Reference Guide (QRG), which is a summary of the main recommendations
in the NICE guideline. For printed copies, phone NICE publications on 0845 003 7783
or email publications@nice.org.uk
Understanding NICE Guidance (UNG), which describes the guideline using nontechnical language. It is written chiefly for people suspected of, or diagnosed with,
ovarian cancer but may also be useful for family members, advocates or those who
care for patients with cancer of unknown primary. For printed copies, phone NICE
publications on 0845 003 7783 or email publications@nice.org.uk
xxi
Updating the Guideline

Literature searches were repeated for all of the clinical questions at the end of the GDG
development process, allowing any relevant papers published before 16 July 2010 to be
considered. Future guideline updates will consider evidence published after this cut-off
date.
Three years after publication of the guideline, NICE will commission a National
Collaborating Centre to determine whether the evidence base has progressed significantly
to alter the guideline recommendations and warrant an early update.
Funding
The National Collaborating Centre for Cancer was commissioned by NICE to develop this
guideline. Health economic analysis for this guideline was provided by the London School
of Hygiene and Tropical Medicine and funded by the National Collaborating Centre for
Cancer.
Disclaimer
The GDG assumes that healthcare professionals will use clinical judgment, knowledge and
expertise when deciding whether it is appropriate to apply these guidelines. The
recommendations cited here are a guide and may not be appropriate for use in all
situations. The decision to adopt any of the recommendations cited here must be made by
the practitioner in light of individual patient circumstances, the wishes of the patient and
clinical expertise.
The NCC-C disclaims any responsibility for damages arising out of the use or non-use of
these guidelines and the literature used in support of these guidelines.
References
Briggs, A., Claxton K, Sculpher M, Decision Modelling for Health Economic Evaluation. 2006, Oxford: Oxford University Press.
National Institute for Health and Clinical Excellence (2009) The guidelines manual. London: National Institute for Health and
Clinical Excellence.
xxii
Algorithms
Support and information
Overview of pathway
xxiii
xxiv
Refer urgently1, 3
Suggestive of ovarian cancer
Arrange ultrasound of
abdomen and pelvis
> 35 IU/ml
Yes
Investigate
Normal
No
Symptoms not suggestive

of ovarian cancer
Advise the woman to return if symptoms

become more frequent and/or persistent
No
Assess carefully: are

other clinical causes
of symptoms
apparent?
< 35 IU/ml
Yes
Ovarian cancer
suspected?
Woman reports any of the following

symptoms:
unexplained weight loss
fatigue
changes in bowel habit
Measure serum CA125
Woman reports having any of the following symptoms

persistently or frequently particularly more than 12
times per month (especially if she is 50 or over)1:
persistent abdominal distension (bloating)
increased urinary urgency and/or frequency
Or:
Woman is 50 or over and has had symptoms within the
last 12 months that suggest irritable bowel syndrome2
Woman presents to GP
See also Referral guidelines for suspected cancer (NICE clinical guideline 27; available at www.nice.org.uk/guidance/CG27) for recommendations about the support and information needs of people with
suspected cancer.
2
See Irritable bowel syndrome in adults (NICE clinical guideline 61; available at www.nice.org.uk/guidance/CG61). Irritable bowel syndrome rarely presents for the first time in women of this age
3
An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks.
Physical examination identifies

ascites and/or a pelvic or
abdominal mass (not obviously
uterine fibroids)
Algorithms
Tests in secondary care
See Box 3.1 for details of how to calculate an RMI I (risk of malignancy index I) score
xxv
Epidemiology
1.1
Introduction
This chapter provides a summary of the needs assessment that was carried out to inform
development of this guideline and includes current information regarding the epidemiology
of ovarian cancer.
1.2
Data collection
Office of National Statistics (ONS) and cancer registries
The data on incidence, mortality and survival of ovarian cancer for the United Kingdom is
published by the ONS (2007). It is based on the data collated by 11 cancer registries
covering England, Wales, Scotland and Northern Ireland (Department of Health, 2008).
Sources for this data include general hospitals, cancer centres, hospices, private hospitals,
cancer screening programmes, primary care, nursing homes and death certificates. The
minimum dataset of information includes:
Patient details (name, date of birth, NHS number, address, ethnicity and sex)
Hospital details (hospital, consultant and patient unit number)
Diagnostic, tumour and treatment details (site and type of primary tumour, laterality,
stage and grade of the tumour, and some treatment information)
Death details (date of death, cause and place of death and post mortem information).
There is approximately a two year gap between the event time and the publication of the
summary statistics. There is a high degree of completeness in terms of diagnosis and deaths.
However, the completeness and quality of data collected on a specific individual and their
cancer can be variable.
Registries record information about cancers apparent at the time of diagnosis of the primary
neoplasm. However, they do not always record information about management and
treatment received. Consequently national data on the management of ovarian cancer is
sparse
Some international data are available from GLOBOCAN and EUROCARE and are valuable
for the purpose of comparison. The GLOBOCAN project provides contemporary estimates
of the incidence of, and mortality from the major types of cancer at a national level, for all
countries of the world. The GLOBOCAN estimates are presented for 2008 separately by sex
and for all ages. These are calculated from the recent data provided by the International
Agency of Research for Cancer (IARC)1. The EUROCARE project seeks to standardise the
cancer survival data across Europe in order to provide meaningful comparisons between
countries (Berrino, 2003). An important point to remember when looking at the results is
that cancer registration in several European countries only covers a small proportion of the
total national population. Summary results for these countries may not therefore represent
the situation in the country as a whole and hence might not be a true comparison (Berrino
et al., 2009).
http://globocan.iarc.fr/
Hospital inpatient care

In England, the Hospital Episode Statistics (HES) record information on all NHS admissions.
These include all day case and inpatient admissions to NHS hospitals (including private
patients and non-UK residents) and admissions to independent providers commissioned by
the NHS. The information recorded includes patient demographic information, diagnosis
for each admission and date and length of admission. A similar system, Patient Episode
Database Wales (PEDW) operates in Wales.
The data is processed nationally to remove duplicates and any obvious errors in order to
provide the most robust data possible. The quality of the data is only as good as the quality
of data entry and this may vary between providers. Systematic misclassification will occur
but it is not possible to quantify and its effect is unknown. The Welsh Cancer Intelligence
and Surveillance Unit (WCISU) has combined their registry and HES/PEDW data to obtain
information on the treatment received by ovarian cancer patients in their locality. There is a
similar project being carried out in England by the Trent Cancer Registry and the results are
expected later this year.
Hospital outpatient care

Outpatient data have also been collected through the HES and PEDW dataset since 2003.
These data record the speciality associated with the appointment but does not record the
particular investigation carried out or the results of the appointment and so have not been
examined as part of this needs assessment.
1.3
Incidence
Ovarian cancer is the fifth commonest cancer in women in the UK after breast, colorectal,
lung and uterus. Approximately 6,700 new cases of ovarian cancer were diagnosed every
year in United Kingdom between 2004 and 2007 accounting for approximately 1 in 20
cases of cancer in women (Walsh and Cooper, 2005).
Incidence in the UK, constituent countries and cancer networks

Data in Table 1.1 show that in 2007 6,719 new cases of ovarian cancer were diagnosed in
the UK which equates to a crude rate of 21.6 per 100,000 population. The European age
standardised incidence rate (EASR) is 17.0 per 100,000 population. There are slight
variations in the incidence rate across the constituent countries of the UK. Wales has a
higher incidence rate compared to the national rates and Northern Ireland the lowest (14.2
per 100,000 population).
Table 1.1 Number of new cases and rates registered for ovarian cancer in 2007.
Cases
England
Wales
Scotland
N.Ireland
United Kingdom
5,566
381
625
147
6,719
25.0
23.5
16.4
21.6
18.4
17.8
14.2
17.0
Crude rate per 100,000 21.4

population
Age-standardised rate
(European) per 100,000 17.0
population
95% CI
16.617.4 16.620.3
16.419.2 11.916.5
16.617.5
Data source: Reproduced from Cancer Research UK.
The latest data of incidence rate by cancer network is from 2005 (Figure 1.1). Comparing
networks within England, the incidence rate was highest in the North London Cancer
Network with a rate of 24.3 per 100,000 population. The lowest incidence rate was noted
in the North of Scotland with an incidence rate of 12.0. All cancer networks in Wales had
Epidemiology
rates higher than the UK average. These differences in the incidence rates across the UK
may have arisen from differences in diagnostic criteria or cancer registration or both.
30
25
20
15
10
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N
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Age-standarised Incidence rates per 100,000
Figure 1.1 Age-standardised incidence rates of ovarian cancer by Welsh and English Cancer
Network, Scotland and Northern Ireland (2005).
Incidence Rate
Data sources: ISD Scotland, Northern Ireland Cancer Registry, UK Association of Cancer Registries, Welsh Cancer
Intelligence and Surveillance.
These data include borderline malignancies. A further confounding issue is that primary
peritoneal cancer and metastatic malignant disease of unknown primary origin may also be
included.
European and Worldwide comparison

Figure 1.2 shows the incidence rates of ovarian cancer across the world in 2008. The
United Kingdom has a relatively high incidence rate of up to 14.6 per 100,000 population.
The incidence rates are highest in Central America and Northern Europe and lowest in
some parts of Africa and Asia.
Figure 1.2 Worldwide estimated age-standardised incidence rate of ovarian cancer per
100,000 population; all ages (2008).
Data source: GLOBOCAN 2008 (IARC).
In comparison with other European countries, the UK is among those with the highest
incidence rates of ovarian cancer (Figure 1.3). Generally the highest rates are in the
Northern and Eastern European countries of Lithuania, Latvia, Ireland, Slovakia and Czech
Republic. The lowest rates are in Southern European countries of Portugal and Cyprus.
Figure 1.3 Age-standardised incidence rates of ovarian cancer in the European Union
(2008).
United Kingdom
The Netherlands
Sweden
Spain
Slovenia
Slovakia
Portugal
Poland
Malta
Luxembourg
Lithuania
Latvia
Italy
Ireland
Hungary
Greece
Germany
France
Finland
Estonia
Denmark
Incidence
Czech Republic
Cyprus
Belgium
Austria
0
10
15
20
25
Rate per 100,000 females
Data source: Globocan 2008 (IARC).
Incidence rates of ovarian cancer by age

The lifetime risk of women being diagnosed with ovarian cancer is 1 in 48 (Walsh and Cooper,
2005). The data in Figure 1.4 show that overall 90% of the ovarian cancer recorded in the UK in
2007 were in women aged 45 years and above. The incidence rates are higher in postmenopausal
women, with the highest in the age group of 6064 years of age.
Figure 1.4 Number of new cases diagnosed and incidence rate of ovarian cancer by age in
the United Kingdom (2007).
1,000
80
Age at diagnosis
Data source: Office for National Statistics.
85+
80-84
75-79
70-74
65-69
60-64
55-59
50-54
45-49
40-44
5-9
0-4
35-39
20
30-34
250
25-29
40
20-24
500
15-19
60
Rate per 100,000 population
Female rates
750
10-14
Number of cases
Female cases
Epidemiology
Trends in incidence rates of ovarian cancer

The age standardised incidence rates of ovarian cancer have increased in the UK from 14.7
in 1975 to 16.4 in 2007 (Figure 1.5). Incidence rates peaked around 19951999 and this
may be associated with the inclusion of cancer of borderline malignancy within the
category of malignant cancer according to International Classification of Disease for
Oncology (ICDO2). The ICDO2 was introduced in England and Wales in 1995, Scotland in
1997 and Northern Ireland in 1996. This could also explain the rising trend of incidence
rates after 1996.
Figure 1.5 Trends in age standardised incidence rates of ovarian cancer (19752007).
25.0
20.0
15.0
Incidence
10.0
5.0
19
75
19
77
19
79
19
81
19
83
19
85
19
87
19
89
19
91
19
93
19
95
19
97
19
99
20
01
20
03
20
05
20
07
0.0
Year
Data Source: Cancer Research UK.
Socioeconomic status and ethnicity

Socioeconomic status has no affect on incidence of ovarian cancer (Figure 1.6).
The National Cancer Intelligence Network (NCIN) recently published a report analysing the
relationship between cancer incidence and ethnicity in those diagnosed with cancer in
England (2002-2006) (NCIN, 2009). It showed Asian and Black ethnic groups have lower
incidence rates of ovarian cancer compared to the White ethnic group. The analysis was
presented only on Asian, Black and White ethnic group due to the small number of Chinese
and Mixed ethnic groups in the study.
Figure 1.6 Ovarian cancer incidence by deprivation quintile, England (2000-2004).
Age Standarised Incidence Rate
30
25
20
15
10
5
0
Least Deprived
Most Deprived
Overall
Data source: NCIN 2009.
1.4
Mortality
Approximately 4,300 women die from ovarian cancer each year in the UK which makes it
the leading cause of death in gynaecological cancers (Cancer Research UK2). It accounts for
6% of all cancer deaths in women. The reason for the high mortality rate in ovarian cancer
http://info.cancerresearchuk.org/cancerstats/index.htm
may be because most women are diagnosed with advanced ovarian cancer at the time of
detection.
Mortality rates in the United Kingdom

The age-standardised mortality rates are similar across all countries within the UK with an
overall average of 9.7 (Table 1.2). The highest mortality rate is seen in Northern Ireland
(11.0) compared to the UK average. Wales has the lowest mortality rate in spite of a high
incidence rate (see Table 1.1).
Table 1.2 Number of deaths and European age-standardised mortality rates of ovarian
cancer per 100,000 population in the UK (2008).
England
Wales
Scotland
N. Ireland
United Kingdom
Deaths
3,609
215
423
126
4,373
Crude rate per 100,000

population
13.8
14.0
15.9
13.9
14.0
Age-standardised rate
(European) per 100,000
population
9.6
9.3
10.4
11.0
9.7
95% CI
9.3-9.9
8.1-10.5
9.4-11.4
9.1-12.9
9.4-10.0
Data sources: Office of National Statistics, reproduced from Cancer Research UK
Mortality rates by cancer network

The mortality rate of ovarian cancer by cancer network in 2005 was highest in the
Peninsula and Mid Trent Cancer Network and lowest in the North London, West London
and North East London Cancer Networks (Figure 1.7).
Age-standarised Mortality rate per 100,000 population

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rk he nd
So
s
rre
s C
ut M hire hir N
y,
h
o
W
C e
es C Ea unt oa CN
t S en st Ve st
us tra of S rn CN
se l S c on
x ou otl C
a n t h an N
d
Pa d H Co C
n am a s N
Bi p t C
La
rm s h N
nc
i
in re
ha
gh C
sh
am N
ire N
an orth W CN
d
So Wa ale
ut les s
h
c CN
S u um
ss bria
e
D
er Ar x C
by d N
N /B en
or ur C
th to N
er n
n CN
Ire
Pe Es lan
n n s ex d
So
in
ut M su CN
h id la
Ea T C
st ren N
W tC
al N
es
C
N
Figure 1.7 Age-standardised mortality rates of ovarian cancer by cancer network in the UK
(2005).
14
12
10
8
6
4
2
0
Data sources: ISD Scotland; Northern Ireland Cancer Registry; UK Association of Cancer Registries; Welsh Cancer
Intelligence and Surveillance Unit; NCIN 2008
Mortality rates and number of deaths by age

Data in Figure 1.8 show the number of deaths and mortality rate by age in the UK in 2008.
The number of deaths is highest in 70-74 years age group, but the highest mortality rates
are in the 80-84 years age group.
Epidemiology
700
70.0
600
60.0
500
50.0
400
40.0
300
30.0
200
20.0
100
10.0
85+
80-84
75-79
70-74
65-69
55-59
60-64
50-54
40-44
45-49
35-39
30-34
25-29
20-24
15-19
10-14
5-9
0.0
0-4
Age-speci fi c rates per

wom en 100, 000
Num ber of deaths
Figure 1.8 Number of deaths and mortality rate of ovarian cancer in the UK by age (2008).
Age
Worldwide and European comparisons

The global and European data in this section for ovarian cancer are contemporary estimates
from the GLOBOCAN project (Figure 1.9). The advantage of global data is national
coverage and long-term availability. However, the data quality varies considerably. These
data indicate that the United Kingdom and Ireland have comparatively high mortality rates
even when compared to other European countries.
Figure 1.9 Worldwide estimated age-standardised mortality rate of ovarian cancer per
100,000 population, all ages (2008).
Across Europe, the highest mortality rates are seen in Northern Europe and Ireland (Figure
1.10). This is similar to the high incidence rates seen in these regions.
Figure 1.10 Estimated age-standardised mortality rate of ovarian cancer, European Union
(2008).
United Kingdom
The
Sweden
Spain
Slovenia
Slovakia
Portugal
Poland
Malta
Luxembourg
Lithuania
Latvia
Italy
Ireland
Hungary
Greece
Germany
France
Finland
Estonia
Denmark
Czech Republic
Cyprus
Belgium
Austria
0.0
2.0
4.0
6.0
8.0
10.0
Age-standardised mortality rates

Trends in mortality rates and numbers of deaths from ovarian cancer

Data in Figure 1.11 show the trends in the age-specific mortality rate of ovarian cancer
from 1971 to 2008. The trends vary across the different age groups. The mortality rate
shows a gradual increase in women over 65 years of age with some decline in younger
women. It is evident from the graph that the mortality rate has been fairly stable over the
last 10 years in women under 49 years of age compared to the age group of 50-64 years
where there has been a steady decline. Overall mortality rate of ovarian cancer remains
relatively stable in spite of the increasing incidence.
Figure 1.11 Trends in age specific mortality rate of ovarian cancer by age in United
Kingdom (1971-2008).
Rate per 100,000 population
70
15-39
40-49
50-64
65+
Overall mortality
60
50
40
30
20
10
Year of death
2007
2004
2001
1998
1995
1992
1989
1986
1983
1980
1977
1974
1971
Epidemiology
Survival
Most women are diagnosed with advanced stage disease and this contributes to ovarian
cancer having the lowest relative five year survival rate of all gynaecological cancers (ONS
2007).
Trends in survival rates from ovarian cancer

The five year survival rates for patients with ovarian cancer have increased dramatically
from 20% in 1975 to 38.9% in 2006 (Figure 1.12). A similar trend has been observed in ten
year survival rate from 20% between 1971-1975 to 33.3% between 1996-2000 (Figure
1.13). The two fold increase in the survival rate may be due to early detection methods,
improved treatment modalities, or inclusion of borderline tumours which have a good
prognosis (ONS 2007; Richard 2008; Rachet et al., 2009).
Figure 1.12 Trends in the age-standardised one year, five year and ten year (1971-2000)
survival rate of ovarian cancer in England and Wales (1971-2006).
80
70
60
Relative Survival Rate
1.5
50
year -1
year -5
year -10
40
30
20
10
0
1971-1975
1976-1980
1981-1985
1986-1990
1991-1995
1996-1999*
20012006**
(* England only data, ** shows one year survival between 2001-2003 and five year survival between 2001-2006)
Data source: Office of National Statistics and Cancer Research UK
Survival rate by age at diagnosis

The survival rate based on age at diagnosis is shown in Figure 1.13. Both the one-year and
five year survival are higher in young women (15-39) compared to older women (>40). In
women aged 15-39 years the one year and five year survival are 93% and 84% respectively
compared to 31% and 14% in the 80-89 age group.
Figure 1.13 Age-standardised five year relative survival of ovarian cancer by age in England
(2001-2006).
Age standardised relative survival rate
90
80
70
60
50
Five-year survival
40
30
20
10
0
15-39
40-49
50-59
60-69
70-79
80-99
Age
Data source: Office of National Statistics-Statistical Bulletin Cancer survival in England (Berrino 2003; Berrino et al., 2009)
International comparison
In this section international data are presented from EUROCARE and the International Cancer
Benchmarking Partnership (ICBP) and are valuable for the purpose of comparison. The
EUROCARE project seeks to standardise the cancer survival data across Europe in order to
provide meaningful comparisons between countries (Berrino, 2003). The ICBP compares 12
jurisdictions in six countries with comprehensive cancer registration, and broadly similar
healthcare systems. The ICBP is also the most up to date international survival comparison
providing data from 1995 to 2007, whereas the main EUROCARE studies completed in 1999.
In an international comparison of women diagnosed with ovarian cancer in 19951999,
the survival rates in England, Wales, Scotland and Northern Ireland were significantly lower
than the European average (Figure 1.14). A more up to date study from 19952007 reported
an increase in survival in England, Wales and Northern Ireland, but a persistent gap in five
year survival between the UK nations and Norway, Australia and Canada (Figure 1.15)
(ICBP, 2011). It has been estimated that the 5 year ovarian cancer survival gap compared to
the best in Europe accounts for 500 avoidable deaths a year (Abdel-Rahman et al., 2009).
Figure 1.14 Relative five year survival rate, cumulative of ovarian cancer for women aged
15-99 years diagnosed 1995-1999 across Europe.
Re l a t i v e su r v i v a l r a t e , C u m u l a t i v e
60
50
40
30
20
10
Cz
e
ch
Be
Au
st
r
ia
lg
Re i um
pu
D b li
en c
m
a
Fi r k
nl
an
Fr d
a
G nc
er
e
m
a
Ic ny
el
an
Ir d
el
an
d
It
al
y
N
et Ma
he l t
r la a
n
N ds
or
w
a
Po y
la
Po n d
rt
u
Sl g a
ov l
en
ia
Sp
Sw a i n
Sw e
i t z d en
U
K
e
N U K r la
or
t h En n d
er g l
an
n
d
I
U r el
K
an
S
co d
U t la n
K
W d
a
Sl l e s
ov
ak
Eu i a
ro
pe
Data source: Eurocare 4 Database
10
Epidemiology
Figure 1.15. Relative five year age standardized survival rate (Australia = New South Wales,
Victoria, Canada = Alberta, British Columbia, Ontario, Manitoba, UK = England, Wales,
Northern Ireland).
45
CAN
40
NOR
AUS
UK
DEN
35
30
1995-99
2000-02
2005-07
Data source: ICBP, 2011
Survival by stage
Ovarian cancer is staged using the FIGO classification (Box 1.1), based on the information
obtained from surgery, supplemented by imaging information where appropriate. Optimum
surgical staging comprises midline laparotomy to allow thorough assessment of the
abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and
infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic
and abdominal peritoneum and retroperitoneal lymph node assessment (Winter-Roach et
al., 2009). Cancer registries use TNM classification similar to FIGO staging.
Box 1.1 FIGO staging for ovarian cancer
Stage I: limited to one or both ovaries
Ia
1b
1c
involves one ovary; capsule intact; no tumour on ovarian surface; no malignant cells in ascites
or peritoneal washings
involves both ovaries; capsule intact; no tumour on ovarian surface; negative washings
tumour limited to ovaries with any of the following: capsule ruptured, tumour on ovarian
surface, positive washings
Stage II: pelvic extension or implants

IIa
IIb
IIc
extension or implants onto uterus or fallopian tube; negative washings

extension or implants onto other pelvic structures; negative washings
pelvic extension of implants with positive peritoneal washings
Stage III: microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with
extension to the small bowel or omentum
IIIa
IIIb
IIIc
microscopic peritoneal metastases beyond pelvis

macroscopic peritoneal metastases beyond pelvis less than 2 cm in size
peritoneal metastases beyond pelvis >2 cm or lymph node metastases
Stage IV: distant metastases to the liver or outside the peritoneal cavity
Currently there is only data available in Wales on the stage at presentation for women with
ovarian cancer. Data from WCISU showed that only 10-20% of staging data are recorded
on their Cancer registry database for patients with ovarian cancer (Figure 1.16). This makes
statistical analysis based on staging difficult. Data from England is expected and has yet to
be published.
11
Figure 1.16 Ovarian cancer by stage, Wales (2000-2007).
2007
2006
2005
Year
Stage 1
Stage 2
Stage 3
Stage 4
Unknown
2004
2003
2002
2001
2000
0%
20%
40%
60%
80%
100%
Number
Data source: WCISU
Socioeconomic status and ethnicity

Among adults living in the most deprived areas who were diagnosed cancer between 1981
and 1990, 5-year survival was significantly lower than for those in the most affluent areas
for 44 of 47 different cancers (Coleman et al., 1999). More recent data would suggest that
whilst there still remains a gap in survival at one year in women living in deprived areas,
this has largely disappeared in terms of five year survival. The gap at one year may well
relate to presentation with advanced disease combined with poor access to appropriate
treatment. Improvement in the latter (Cooper et al., 2008) may be reflective of improved
access to specialist treatment.
1.6
Routes to diagnosis
For all patients diagnosed with cancer in England in 2007, the National Cancer Intelligence
Network (NCIN) has published data on the different routes taken by patients to their cancer
diagnosis (NCIN, 2010). Data in Table 1.3 highlights a wide variation in routes to diagnosis
for ovarian cancer patients and shows that the majority of patients attend electively,
however a significant proportion attend as emergencies. A large proportion of elective
admissions present outside the urgent (two week) referral pathway.
Table 1.3 Routes to diagnosis for ovarian cancer, England (2007).
Cancer
Two
GP
Other
Inpatient
Emergency
Death
type
Week
referral
outpatient
elective
presentation
Certificate
Wait
Ovary
26%
Unknown
Total
Number of
patients
Only
22%
15%
1%
29%
1%
6%
100%
5012
Courtesy: Route to Diagnosis, NCIN data briefing, November 2010.
1.7
Treatment
Ovarian cancer is managed using a number of treatments which usually comprise
chemotherapy or surgery often in combination. As there was no available comparative
national data on treatment modalities, a questionnaire was developed by the GDG and sent
to all cancer networks. Only two cancer networks were able to provide data on treatments
used. In one region it appeared that up to 40% of patients are managed with chemotherapy
alone (this had an association with age). In the other region there was marked variation
between hospitals and within hospitals over time in the proportion of patients receiving
chemotherapy. The reason for this variation is not understood.
12
Epidemiology
Surgery
Currently there is only data available in Wales on the surgical management of women with
ovarian cancer. Data from England is expected and yet to be published.
WCISU recently combined PEDW data on the surgical management of women with
ovarian cancer using data from the financial years 2004 to 2009. There were a total of
1919 women diagnosed with ovarian cancer during that time.
Figure 1.17 illustrates the different procedures carried out in the three cancer networks in
Wales. The most frequent procedure undertaken involves total abdominal hysterectomy,
bilateral salphingo-oopherectomy and omentectomy as this involves the staging
laparotomy.
Figure 1.17 Number of different surgical procedures performed for ovarian cancer by
cancer network, Wales (2004-2008).
Surgical Procedures
Omentectomy
Supraracolic
Removal of
unilateral
ovaries
North Wales
South West Wales
South East wales
Bilateral
removal of
ovaries
Total
abdominal
hysterectomy
0
100
200
300
400
Number of procedures
Data source: WCISU
1.8
The findings of cancer peer review of gynaecology cancer teams

in England 2004-2007
The Calman-Hine report on a Policy Framework for Commissioning Cancer Services
published in 1995 and the series of NICE Improving Outcome Guidance formed the basis
of establishing national standards for cancer care in England. This led to the establishment
of a National Cancer Peer Review (NCPR) process which is a national quality assurance
programme for NHS cancer services in England. It aims to improve the care of the patients
with cancer and their families. This is done through self-assessment by cancer service teams
and external review by professional peers against nationally agreed quality peer review
measures.
The first programme of review focussed on services in four tumour site areas; breast, lung,
colorectal, gynaecology and was coordinated on a regional rather than national basis. The
programme was independently evaluated, the results of which informed the development
of the 2004-08 National Cancer Peer Review Programme.
Currently the NCPR programme consists of the three key stages illustrated in the Figure
1.18.
13
Figure 1.18 Stages of the National Cancer Peer Review Programme on gynaecology cancer
teams (2004-2008).
All cancer networks in England and all their designated local and specialist Gynaecology
cancer teams were reviewed against the national standards by a team of clinical peers
between 2004 and 2008. The reports of these reviews are available publicly via the
CQuiNS website3.. The review was for all gynaecological cancers and not for ovarian
cancer alone. During the targeted visit, the peer group reviewed whether each measure is
achieved or not and whether overall progress is being made toward the achievement of the
standards. Following the outcome of the review, the cancer networks should agree actions
in order to meet those standards not currently being met achieved within defined
timescales.
The results of the most recent peer review process in England (2009-2010) were published
by the National Cancer Action Team (NCAT) in October 2010 and included a separate
report for gynaecology MDTs. They reported that MDTs have improved their overall
compliance against the measures since the 2004/2008 peer review round by 11%. A
summary of all the findings can be found in the full report (NCAT, 2010).
1.9
Summary
Ovarian cancer is the second most common gynaecological cancer in the UK accounting
for over 6,700 new cases diagnosed each year. The rates have been steadily increasing over
the past 20-25 years, with a notable increase in the 65 years and above age group. There is
some geographic variation in the incidence rate across the UK. This may be due to
variation in diagnostic criteria, cancer registration or population.
Ovarian cancer is the leading cause of death in women with gynaecological cancer and
accounts for 6% of all deaths in women. The mortality rate remains almost the same in all
regions of the UK. There has been a two fold increase in the survival rate over the last two
decades which might reflect better diagnostic and treatment methods.
The process of producing this report has highlighted the lack of data available to assess the
burden of the disease based on the stage and the type of ovarian cancer. It is clear that
there are difficulties in the collection and definitions in the minimum dataset for ovarian
cancer. This deficiency makes the interpretation of effectiveness of treatments highly
uncertain and is an important obstacle to improving cancer care for women with ovarian
cancer.
14
www.cquins.nhs.uk
Epidemiology
References
Abdel-Rahman M., Stockton D., Rachet B., Hakulinen T., and Coleman MP (2009) What if cancer survival in Britain were the same
as in Europe: how many deaths are avoidable? British Journal of Cancer 101 (Suppl 2): S11524.
Berrino F (2003) The EUROCARE study: strengths, limitation and perspectives of population bases, comparative survival studies.
Annals of Oncology 14: 913
Berrino F., Verdecchia A., Lutz J.M., et al.,: the EUROCARE working group (2009) Comparative cancer survival information in
Europe. European Journal of Cancer 45: 901908.
Coleman MP., Babb P., Damiecki P., et al., (1999) Cancer Survival Trends in England and Wales 19711995: Deprivation and
NHS Region. London: The Stationery Office; Series SMPS No. 61.
Coleman MP., Forman D., Bryant H., Butler J., Rachet B., Maringe C., Nur U., Tracey E., Coory M., Hatcher J., McGahan CE.,
Turner D., Marrett L., Gjerstorff ML., Johannesen TB., Adolfsson J., Lambe M., Lawrence G., Meechan D., Morris EJ., Middleton R.,
Steward J., Richards MA,. ICBP Module 1 Working Group (2010) Cancer survival in Australia, Canada, Denmark, Norway,
Sweden, and the UK, 19952007. The International Cancer Benchmarking Partnership: an analysis of population-based cancer
registry data. Lancet. 377(9760):12738
Cooper N., Quinn MJ., Rachet B., et al., (2008) Survival from cancer of the ovary in England and Wales up to 2001. British Journal
of Cancer 99: S70S72
Department of Health (2008) The national cancer registration system 2008.
Elliss-Brookes L. (2010) Routes to Diagnosis results: presentation at UKACR and NCIN joint conference. Available at
http://www.library.ncin.org.uk/docs/RtD_NCIN_18thJune10_LEB.pdf
NCAT (2010) National cancer peer review programme. Report 2009/2010. An overview of the findings from the 2009/2010
National Cancer Peer review of Cancer Services in England. Available at:
http://ncat.nhs.uk/sites/default/files/_resources_reports_NCAT_NCPR_National_Report_2009_10.pdf
NCIN (2009) Cancer incidence and survival by major ethnic group, England, 2002-2006: incidence rate ratios and estimated ASRs.
NCIN (2008) Cancer incidence and mortality by cancer network, UK, 2005. http://library.ncin.org.uk/docs/081007-NCINUK_Incidence_Mortality_05-Report.pdf
NCIN (2010) Routes to diagnosis NCIN data briefing. Available at
http://www.ncin.org.uk/publications/data_briefings/routes_to_diagnosis.aspx
Office for National Statistics (ONS) (2007) Survival Rates in England, patients diagnosed 20012006 followed up to 2007.
Available at http://www.statistics.gov.uk/statbase/product.asp?vlnk=14007
ONS (2007) Cancer statistics registrations: registrations of cancer diagnosed in 2007. England. Series MB1 no.38.
Rachet B., Maringe C., Nur U. et al., 2009. Population-based cancer survival trends in England and Wales up to 2007:an
assessment of the NHS cancer plan for England. The Lancet Oncology. 10(4): 351369.
Richard MA. (2008) Trends and inequalities in survival for 20 cancers in England and Wales 19862001: population-based
analyses and clinical commentaries . British Journal Cancer. 99 (Supp 1): S1.
Walsh P. and Cooper N. (2005) Ovary, Cancer Atlas of the United Kingdom and Ireland 19912000. p: 193201
Winter-Roach BA., Kitchener HC and Dickinson HO (2009). Adjuvant (post-surgery) chemotherapy for early stage epithelial
ovarian cancer. Cochrane DB Sys Rev 2009, Issue 3. Art. No: CD004706. DOI: 10.1002/14651858.CD004706.pub3.
15
2 Detection in
primary care
The challenge presented by ovarian cancer is to make the correct diagnosis as early as
possible despite the non-specific nature of symptoms and signs. It is therefore important to
establish those symptoms and signs which initiate the first best test that will ensure the
woman is directed to the most appropriate clinical pathway.
The two objectives of this chapter were:
1. to identify which symptoms and signs are associated with ovarian cancer to potentially
allow earlier recognition of ovarian cancer in primary care
2. to assess the relationship between the duration of symptoms and ovarian cancer
outcome.
2.1

Early recognition of ovarian cancer symptoms
Ovarian cancer has been termed the silent killer but it is increasingly recognised that the
majority of women with ovarian cancer have symptoms. These symptoms are non-specific
and widely experienced among the general population. However, they have greater
significance in older women (over 50 years of age) and in those with a significant family
history (two or more cases of ovarian or breast cancer diagnosed at an early age in first
degree relatives).
Two important pieces of work have been published on the signs and symptoms of ovarian
cancer which should be considered alongside the recommendations in this guideline. In
2005 NICE published a set of recommendations for GPs for the urgent referral of woman
suspected of having gynaecological cancer, including ovarian cancer (NICE, 2005). This
guideline updates and will replace recommendation 1.7.4 in Referral guidelines for
suspected cancer (NICE clinical guideline 27; published June 2005). NICE are currently
reviewing whether the entire guideline should be updated and a decision is expected in
November 2010.
A more recent programme has been the Department of Health-led National Awareness and
Early Diagnosis Initiative (NAEDI) project in England which coordinates and provides
support to activities and research that promote the earlier diagnosis of cancer. Part of this
initiative has led to the development of Key messages for ovarian cancer for health
professionals1 which aim to raise awareness of signs and symptoms of the disease and
were published in February 2009.
Most women are diagnosed with advanced (stage II-IV) disease that is associated with poor
survival rates. On the other hand a great majority of women with early stage (stage I)
ovarian cancer can be cured.
16
Available at: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_110534
Women with ovarian cancer are often suspected of having gastrointestinal disease such as
irritable bowel syndrome and therefore not investigated, with resulting delays to diagnosis.
However it is now known that women with ovarian cancer experience some symptoms
more frequently, more severely and more persistently than women who do not have the
disease.
Clinical question: What are the symptoms and signs of ovarian cancer?
Clinical evidence
Evidence about symptoms and signs of ovarian cancer came from case control studies.
For practical reasons these studies were retrospective and prone to recall bias. For
example if women with ovarian cancer can recall their symptom history better than
controls, the predictive value of symptoms would be inflated.
A systematic review by Bankhead et al., (2005) estimated that 93% [95%CI: 92% to
94%] of women experienced symptoms before diagnosis. Evidence from case control
studies shows that abdominal pain, abdominal distension, urinary symptoms, abdominal
mass and postmenopausal/abnormal bleeding are more likely to be reported by women
before a diagnosis of ovarian cancer than in women without ovarian cancer (Table 2.1).
Table 2.1 Individual symptoms for ovarian cancer
Symptom
Sensitivity Specificity Positive

predictive
value*
Negative
predictive
value*
Abdominal pain
17% to
64%
99.97% to
99.99%
70% to
95%
0.07% to
0.33%
References
Friedman et al., 2005; Goff

et al., 2004; Hamilton et al.,
2009; Kim et al., 2009; Lurie
et al., 2009; Olson et al.,
2001; Rossing et al., 2010;
Vine et al., 2001
Abdominal
5% to 68% 62% to
0.01% to
99.95% to
Bankhead et al., 2008; Goff
bloating
98%
0.30%
99.98%
et al., 2004; Friedman et al.,
2005; Hamilton et al., 2009
Abdominal
22% to
53% to
0.07% to
99.97% to
Bankhead et al., 2008; Goff
distension
86%
99%
2.26%
99.99%
et al., 2004; Friedman et al.,
2005; Hamilton et al., 2009;
Lurie et al., 2009
Abdominal
16% to
99% to
0.48% to
99.97% to
Hamilton et al., 2009; Lurie et
mass/swelling
33%
100%
11%
99.98%
al., 2009
Urinary
11% to
78% to
0.05% to
99.97% to
Friedman et al., 2005;
frequency or
43%
97%
0.17%
99.98%
Hamilton et al., 2009; Lurie
urgency
et al., 2009; Olson et al.,
2001; Rossing et al., 2010;
Vine et al., 2001
Abnormal or
13% to
96% to
0.13% to
99.97%
Bankhead et al., 2008;
postmenopaus
20%
99%
0.42%
al bleeding
Hamilton et al., 2009; Lurie
et al., 2009; Vine 2001
Loss of appetite
14% to
70% to
0.05% to
99.97%
Bankhead et al., 2008; Lurie et
39%
98%
0.49%
al., 2009; Olson et al., 2001;
Hamilton et al., 2009
*Assuming a prior probability of undiagnosed ovarian cancer of 0.04% (Hamilton et al., 2009)
17
Box 2.1 Definitions of terms used in this section

Sensitivity is the proportion of women with ovarian cancer who experienced the symptom in the
year prior to diagnosis.
Specificity is the proportion of women without ovarian cancer who did not experience the
symptom within the last year.
The prior probability or pre-test probability is the background risk that a woman has
undiagnosed ovarian cancer, regardless of her symptoms. Hamilton et al., (2009) estimated the
prior probability of undiagnosed ovarian cancer in women presenting to primary care (for
symptoms experienced within the previous year) at 0.036%, using UK national incidence data
for ovarian cancer. However, as Hamilton et al., (2009) point out, not all women will present to
primary care in a given year. In Hamiltons study, 10.8% of the control group had not consulted
in primary care over the one year period of the study. For women consulting in primary care the
prior probability of ovarian cancer was estimated at 0.04%.
The positive predictive value (PPV) of a given symptom for ovarian cancer is the proportion of
women with that symptom who have ovarian cancer. For example if a symptom had a PPV of
0.2% for ovarian cancer, 1 in 500 women with that symptom would have ovarian cancer. The
PPV of a symptom for ovarian cancer in those presenting to primary care depends both on the
sensitivity/specificity of the symptom and the background risk of ovarian cancer in this
population.
The negative predictive value (NPV) of a given symptom for ovarian cancer is the proportion of
women without that symptom who do not have ovarian cancer.
The positive predictive value of bloating as a symptom of ovarian cancer showed great
variability, probably due to various definitions of bloating used in the studies (from
intermittent temporary bloating to permanent or continued abdominal distension).
While the sensitivity of individual symptoms for ovarian cancer is low (see Table 2.1) it
can be improved by combining the symptoms (Table 2.2). Hamilton et al., (2009) and
Rossing et al., (2010) noted that 85% of women with ovarian cancer reported at least one
symptom during the year before diagnosis.
The Goff symptom index (Goff et al., 2007) uses a more restrictive definition of symptoms
which incorporates symptom frequency and onset. This improves specificity at the
expense of sensitivity.
Table 2.2 Combining symptoms to improve sensitivity
Symptom
Sensitivity
Specificity
Positive
predictive
value*
Negative
predictive
value*
References
Any
symptom
85%
74% to 85%
0.13% to
0.21%
More than
99.99%
Hamilton et al., (2009); Rossing

et al., (2010)
64% to 69% 88% to 97% 0.20% to

99.99%
Rossing et al., (2010); Goff et
Goff
0.94%
al., (2007); Andersen et al.,
symptom
(2010); Kim et al., (2009)
index
* Assuming a prior probability of undiagnosed ovarian cancer of 0.04% (Hamilton et al., 2009).
Any of the following symptoms for at least a week during the previous year: urinary frequency/urgency,
abdominal distension, abdominal bloating, pelvic/abdominal pain or loss of appetite. Hamilton et al., (2009)
also included postmenopausal or rectal bleeding. Rossing et al., (2010) also included nausea and
diarrhoea/constipation.
Any of the following symptoms at least 12 times a month (but present for less than one year):
pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, and difficulty
eating/feeling full (Goff et al., 2007).
234
2
3
4
National Institute for Health and Clinical Excellence (2008) Irritable bowel syndrome in adults: diagnosis and management of
irritable bowel syndrome in primary care. NICE clinical guideline 61. London: National Institute for Health and Clinical
Excellence.
18
Recommendations
Refer the woman urgently2 if physical examination identifies ascites and/or a
pelvic or abdominal mass (which is not obviously uterine fibroids)3.
Carry out tests in primary care (see section 2.2 on page 21) if a woman
(especially if 50 or over) reports having any of the following symptoms on a
persistent or frequent basis particularly more than 12 times per month3:
Consider carrying out tests in primary care (see section 2.2 on page 21) if a
woman reports unexplained weight loss, fatigue or changes in bowel habit.
Advise any woman who is not suspected of having ovarian cancer to return to
her GP if her symptoms become more frequent and/or persistent.
Carry out appropriate tests for ovarian cancer (see section 2.2 on page 21) in any
woman of 50 or over who has experienced symptoms within the last 12 months
that suggest irritable bowel syndrome (IBS)4, because IBS rarely presents for the
first time in women of this age.
Linking evidence to recommendations

The GDG placed a high value on obtaining a definitive diagnosis of ovarian cancer. It
considered increasing patient and primary care awareness of the symptoms of
ovariancancer to be important. The GDG was aware of the need to achieve a balance
between the increased numbers of women undergoing investigation to achieve this and
the impact on patient morbidity and finite healthcare resources.
The GDG considered that there was reasonable quality, retrospective evidence that
certain symptoms and signs, when experienced frequently and persistently, are suggestive
of a woman having ovarian cancer. It was agreed that identifying those symptoms and
signs which should prompt healthcare professionals to consider ovarian cancer, could
lead to earlier diagnosis. The GDG believed that the potential benefits of earlier diagnosis
could outweigh the potentially increased demand for investigation of women, and
associated anxiety.
The GDG noted that none of the existing scoring systems for symptoms were sufficiently
accurate on their own to initiate an immediate urgent referral. Therefore the GDG took
elements of these scoring systems to identify which symptoms warrant further
investigation in primary care.
The GDG recognised that women who are 50 or over represent a higher risk group for
ovarian cancer on the basis of age alone, but they did not want to use age as a cut point
as this could disadvantage the 20% of women who have ovarian cancer but are younger
than 50. Therefore the GDG highlighted the 50 or over age group in the recommendation
without excluding those who were younger.
Despite the fact that abnormal vaginal bleeding was linked with the existence of ovarian
cancer (Hamilton et al. 2009, Goff et al. 2007) the GDG felt that the urgent clinical
pathway already established for abnormal vaginal bleeding (NICE, 2005) was likely to
detect ovarian cancer as part of that investigation. Therefore they did not include this
symptom in the recommendations.
In the absence of comparative analysis data of cost and outcomes. health economic
evaluation was not feasible.
19
Duration of symptoms and the effect on stage at presentation

It has been suggested that earlier diagnosis in a number of cancers could improve survival
outcome (Thomson and Forman, 2009). However, the natural history of ovarian cancer is
unknown.
Ovarian cancer is the fifth most common cancer in women. A GP with an average size
practice may only see one case of ovarian cancer every five years which makes recognition
of the symptoms and early diagnosis more difficult. This may mean that women visit their
GPs with symptoms of ovarian cancer on several occasions before these are recognised as
significant.
It is not known if earlier recognition and referral will translate into earlier stage at diagnosis.
However, there is general agreement that early symptom identification, with a high index
of suspicion for ovarian cancer, has the potential to improve prognosis.
The GDG explored the evidence to assess the relationship between the duration of
symptoms prior to diagnosis and the survival rates in ovarian cancer.
Clinical question: What is the relationship between the duration of

pre-diagnostic symptoms of ovarian cancer and survival?
Clinical evidence
Duration of symptoms and stage at diagnosis
Low quality evidence, from retrospective observational studies, suggests women
presenting with advanced ovarian cancer experience a similar duration of symptoms to
those presenting with early stage disease.
Six studies compared the duration of symptoms according to disease stage at diagnosis
(Fruchter et al. 1981; Menczer et al., 2009; Goff et al., 2000; Olsen et al., 2007;
Robinson et al. 1984; Webb et al., 2004). None of these studies found a statistically
significant difference between the duration of symptoms of women presenting with early
and advanced disease.
Olson et al. (2001) found the duration of symptoms before diagnosis was shorter in
women with advanced stage (III to IV) than for early stage (I to II) ovarian cancer for all
their symptom categories, except constipation. This difference was not statistically
significant, however, except for diarrhoea.
Goff et al. (2000) reported that women with early stage disease at diagnosis were less
likely to report ignoring their symptoms than women with advanced stage disease at
diagnosis (74% versus 85%, P=0.002), although there was no significant difference in the
time from symptom onset to diagnosis in early versus advanced stage in their study
(P=0.56).
Neal et al. (2007) analysed the stage at diagnosis of patients with ovarian cancer
according to their referral pathway. There was no significant difference between the stage
at diagnosis of urgent guideline referrals and patients diagnosed through other routes
(P=0.52).
Duration of symptoms, quality of life and survival
Notwithstanding the particular importance of this clinical question to patients and
healthcare professionals, there was insufficient evidence to say whether the duration of
symptoms before diagnosis affects overall survival, quality of life or disease specific
survival.
20
Research recommendation
Further research should be undertaken on the relationship between the duration and
frequency of symptoms in women with ovarian cancer before diagnosis, the stage of
disease at diagnosis and subsequent survival.

The GDG acknowledged the lack of available evidence on the outcomes of interest.
However, the GDG placed a high value on the potential benefits to be derived from an
improved understanding of the relationship between the duration of symptoms and
subsequent outcomes.
Examination of all the evidence found no association, one way or the other, between the
duration of symptoms on the outcomes studied. However, the GDG felt strongly that this
lack of evidence should not preclude timely and appropriate referral.
As this clinical question addressed an epidemiological issue it was felt unlikely to lend
itself to health economic evaluation.
2.2

The majority of women with symptoms suggestive of ovarian cancer will not have ovarian
cancer, so symptoms alone are not sufficient to refer to secondary care. Given the
increased emphasis on symptom recognition this has to be combined with effective
assessment to enable timely and appropriate referral onto the ovarian cancer pathway.
There is con`siderable variation in practice across the UK as to what tests are currently
performed in primary care. In addition many women are referred to other specialists in
error.
The GDG sought to identify the next steps in primary care, given the resources available to
GPs.
Further test options included pelvic examination, serum CA125 or pelvic ultrasound either
individually or in combination.
Clinical examination is an integral part of the assessment of any woman with symptoms.
Whilst this is the case it is also recognised that pelvic examination has limitations in its
ability in detecting adnexal pathology.
A raised serum CA125 in younger women is less likely to be related to a diagnosis of
ovarian cancer and when elevated in this group, can raise considerable worry for patient
and GP alike. A serum CA125 of, for example, >1000 IU/ml in an older postmenopausal
woman is a highly significant finding that points to some sort of malignancy, the most likely
being ovarian or primary peritoneal cancer, although other cancers such as lung or
pancreatic cancer cannot be excluded on this one test alone. In addition serum CA125
levels of several hundred may occur as a consequence of non-malignant conditions such as
heart failure.
Abdomino-pelvic ultrasound is useful for characterising pelvic disease, however, its
unselected use in primary care may place an unsustainable burden on diagnostic resources
and is operator dependent. Because of this, good practice would dictate that ultrasound
scans are performed by a practitioner that is trained and accredited in transabdominal and
transvaginal ultrasound of the pelvis.
21
Clinical question: For women with suspected ovarian cancer, what are the most
effective first tests in primary care?
Clinical evidence
There was no direct evidence comparing serum CA125, morphological ultrasound and
pelvic examination in women with symptoms in primary care. Indirect evidence comes
from systematic reviews of these tests in secondary care or in screening studies. Due to
the differences in case mix between these settings it is likely that the tests will perform
differently in each place.
Assuming a prevalence of ovarian cancer in women with symptoms presenting to

primary care of 0.23%, the positive predictive values of the individual tests were 0.81%
for serum CA125 (Myers et al., 2006) and 1.14% for morphological ultrasound (Liu et al.,
2007). This means that around 1 in every 100 women referred to secondary care with
positive serum CA125 or ultrasound would have ovarian cancer. Negative predictive
values were 99.94% for serum CA125 (Myers et al., 2006) and 99.96% for
morphological ultrasound (Liu et al., 2007), suggesting around 1 in every 2,000 women
with negative tests would turn out to have ovarian cancer.
The evidence suggested pelvic examination is relatively insensitive for the detection of
adnexal masses. Myers et al. (2006) estimated that only 45% of adnexal masses would be
detected on pelvic examination. In women with palpable masses (assuming an ovarian
cancer prevalence of 0.23%), pelvic examination had a positive predictive value of
2.03% for ovarian cancer and a negative predictive value of 99.93% (Myers et al., 2006).
If there is disagreement between the individual tests, there is value in combining them.
Tests can be combined to improve the overall sensitivity at the cost of specificity (by
referring women who are positive on any of the tests). Tests can also be combined to
improve specificity at the cost of sensitivity (by only referring women who are positive on
all the tests).
There was no direct evidence about the performance of combined serum CA125,
ultrasound and pelvic examination in primary care. The accuracy of combined tests was
therefore estimated using the values from the meta-analyses of individual tests and
assuming conditional independence between tests. Combining tests to improve sensitivity
meant a reduced positive predictive value of 0.5% to 0.8% but an improved negative
predictive value of 99.96 to 99.99% (depending on which combination was used).
Using figures from Hamilton et al. (2009) and Bankhead et al. (2005), approximately
0.23% of women with symptoms consistent with ovarian cancer in primary care actually
have ovarian cancer. If all women with symptoms were referred to secondary care,
around 1 in every 500 women referred would turn out to have ovarian cancer.
If women were only referred if they had a positive serum CA125 test or ultrasound scan
(Table 2.3 below), then 1 in every 157 referred would have ovarian cancer (assuming
conditional independence between serum CA125 and ultrasound). 3% of women with
ovarian cancer and symptoms would not be referred.
If women were only referred when both CA125 test and ultrasound were positive, then 1
in every 26 referred would have ovarian cancer. 34% of women with ovarian cancer and
symptoms would not be referred at initial presentation.
22
Table 2.3 Distribution of cases according to test results in a theoretical cohort of 100,000
women with symptoms consistent with ovarian cancer presenting to primary care.
Assumed prevalence of undiagnosed ovarian cancer is 0.23% in women with such
symptoms.
Referral strategy
Test result
Refer if CA125 is positive

CA125 positive
Dont refer if CA125 is negative
CA125 negative
Refer if ultrasound is positive
ultrasound positive
Dont refer if ultrasound is
ultrasound negative
negative
CA125 or ultrasound
Refer if CA125 or ultrasound is
positive*
positive
CA125 and ultrasound
Dont refer if CA125 and
negative*
ultrasound are negative
CA125 and ultrasound
Refer if CA125 and ultrasound
positive*
are positive
CA125 or ultrasound
Dont refer if CA125 or
negative*
ultrasound is negative
* assuming conditional independence
Ovarian cancer
Yes
No
Proportion with ovarian
cancer
179
51
196
34
21,949
77,821
16,961
82,809
223
7
34,920
64,850
0.01%
152
78
3,991
95,779
0.08%
0.81%
0.07%
1.14%
0.04%
0.63%
3.67%
Health economic evaluation (see Appendix 1)

This clinical question was highlighted as a priority for economic analysis because of the
large number of patients with symptoms suggestive of ovarian cancer. In addition there
are significant differences in costs and health outcomes associated with the diagnostic
pathway as well as the considerable economic burden of treating ovarian cancer.
Economic evaluations of a diagnostic investigation require evidence on a number of
issues, including disease prevalence and test accuracy. Furthermore, the accurate
estimation of cost-effectiveness of one diagnostic strategy over another requires
consideration of downstream treatment effects, health-related preferences (utilities),
healthcare resource use and costs. High quality evidence on all relevant parameters is
essential, but not always available. When published evidence is sparse, expert opinion
can be used to estimate relevant parameters. To test the robustness of the results of the
cost-effectiveness analysis, a sensitivity analysis is undertaken.
A decision tree was constructed outlining seven strategies of interest: three of the
strategies consisted of a single test (pelvic examination, ultrasound and serum CA125)
and the remaining four strategies were comprised of a combination of tests (pelvic
examination + serum CA125; pelvic examination + ultrasound; serum CA125 +
ultrasound and pelvic examination + serum CA125 + ultrasound). A Markov process was
embedded in the decision tree to model the recurrence of disease and survival based on
the results of the diagnostic tests and the subsequent management of women presenting
with symptom(s) of ovarian cancer in a primary care setting.
The clinical evidence required to populate the model was obtained from a number of
different sources. Prevalence of the disease in primary care was assumed to comprise of
linear summation of the prevalence of ovarian and colorectal malignancies and benign
gynaecological problems. The estimates of the prevalence of ovarian and colorectal
malignancies were obtained from published literature (CancerResearchUK, 2007;
Hamilton et al., 2009).
The accuracy of the diagnostic procedures, in terms of the corresponding sensitivity and
specificity values, were obtained from the systematic reviews of the clinical evidence
conducted for this guideline (see clinical evidence in sections 2.2 and 2.3) (Hunink and
Glasziou 2001; Bell et al., 1998). There was no consistent reporting of the proportion of
patients in each treatment arm, as defined by the model structure, in the published
literature. Therefore, the estimates of proportion were elicited from the GDG.
23
Effectiveness of treatment in terms of survival and morbidity rates were obtained from
published literature (Kosary 1994; Chien et al., 2005; Gerestein et al., 2009; Loft et al.,
1991; Venesmaa and Ylikorkala 1992; International Collaborative Ovarian Neoplasm
Group 2002). In addition, healthcare resource use associated with providing supportive
care and follow-up monitoring were also obtained via GDG consensus.
Utility weights were required to estimate quality adjusted life years (QALYs). Estimates of
health state utilities specific to ovarian cancer patients were obtained from published
studies (Swart et al., 2007; Tappenden et al., 2007; Drummond et al., 2005).
The costs considered in the analysis were those relevant to the UK NHS, and included
costs of diagnostic investigations (both in primary and secondary care); costs of therapy
(surgery, drug acquisition costs and administration costs) and costs associated with
healthcare resource use for provision of supportive care and follow-up monitoring. Unit
costs were based on NHS Reference Costs 2008-09 or the Unit Costs of Health and
Social Care (PSSRU, 2009).
Within health economic evaluation, discounting of costs and health outcomes is standard
practice where costs and benefits that accrue in the future are given less weight to those
which occur in the present. Following methodological guidance published by NICE, all
costs and health outcomes are discounted at 3.5% per year (PSSRU, 2009).
A summary of expected cost and expected effectiveness estimates associated with each
diagnostic strategy in the model is presented in Table 2.4. The cost of the strategies varies
widely, ranging from the least expensive strategy (serum CA125) at just over 1,500 to
the most expensive (combination of pelvic examination plus serum CA125 plus
ultrasound) at 3,160 per patient. Health outcomes, measured in terms of QALYs, ranged
from 20.391 for the serum CA125 strategy to 19.524 for the pelvic examination plus
serum CA125 plus ultrasound combination strategy. Serum CA125 (single test) strategy
on average generates 20.391 QALYs and ultrasound (single test) generates 20.387 a
difference of 0.004 QALYs is an equivalent (on average) of an additional 1.5 days of
perfect health.
Table 2.4 Base case total expected cost and QALYs
ICER
Strategy
Cost
()
Effectiveness
(QALY)
Serum CA125
1,532.32
20.391
Ultrasound
1,604.24
20.387
(Dominated)
Pelvic examination + serum CA125
1,809.06
20.316
(Dominated)
Pelvic examination + ultrasound
1,864.16
20.298
(Dominated)
Pelvic examination
2,112.49
20.177
(Dominated)
Serum CA125 + ultrasound
2,850.49
19.681
(Dominated)
Pelvic examination + ultrasound + serum CA125
3,160.73
19.524
(Dominated)
ICER incremental cost-effectiveness ratio
All strategies in this analysis are dominated by the serum CA125 strategy. A strategy is
said to be dominated if it is both more costly and less effective than its comparator.
A series of one-way sensitivity analyses were conducted to assess the robustness of the
study results. One-way sensitivity analysis describes the process of changing one
parameter in the model and re-running the model to see how a change in this parameter
influences overall results.
24
Five scenarios were considered and are detailed below:
nationally-agreed drug discounts

a decrease in prevalence of ovarian malignancy in primary care
the prevalence of benign gynaecological problem varied over an agreed range
(20% - 30%)
a decrease in the proportion of patients who are not fit for further treatment following
diagnostic investigation
an increase in age at the start of the model.
The results of the base case analysis were not sensitive to any of the five scenarios
outlined above. The effect of applying nationally agreed price discounts did alter the
overall expected costs but did not alter the ranking of the most cost-effective strategy.
Specifying the parameters as distributions and performing a probabilistic sensitivity
analysis showed that the CA125 strategy did little to alter this conclusion. Similarly, the
results of the one-way sensitivity analysis in the other scenarios showed changes in the
overall expected costs and health benefits but did not alter the ranking of the costeffective diagnostic strategy.
Recommendations
Measure serum CA125 in primary care in women with symptoms that suggest
ovarian cancer (see section 2.1 on page 16).
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the
abdomen and pelvis.
If the ultrasound suggests ovarian cancer, refer the woman urgently5 for further
investigation6.
For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of
35 IU/ml or greater but a normal ultrasound:
assess her carefully for other clinical causes of her symptoms and investigate
if appropriate
56

The recommendations were based on evidence of test performance and a health
economic evaluation of the most cost-effective first test.
The GDG recognised the need for an initial test using an objective and standardised
assessment in symptomatic women because this would reduce observer variability.
Serum tumour markers fulfil these criteria. High value was placed on serum CA125 as it
is currently the most widely used and reliable serum tumour marker for ovarian cancer.
The GDG acknowledged that the clinical evidence was of limited applicability because it
did not come from symptomatic women in primary care. This evidence was based on
data in a secondary care setting. The main difference between the two populations is that
the prevalence of ovarian cancer is lower in primary care than in secondary care.
However, the sensitivity analysis conducted as part of the health economic analysis
showed that changing the prevalence of ovarian cancer in the economic model did not
affect the results. The GDG therefore felt it was appropriate to apply this data in primary
care.
5
6
25
The clinical evidence demonstrated that no single test on its own adequately selected a
manageable number of women for referral to secondary care. The combination of raised
serum CA125 and sequential ultrasound of the abdomen and pelvis reduced significantly
the number of women who would be referred, though a greater proportion of
symptomatic women would be directed to the right pathway in a more timely fashion.
Although the trade off in adopting a sequential strategy as recommended means that
some women with ovarian cancer would be missed in the first instance, the view of the
GDG was that this was a sensible and pragmatic decision as those women whose
symptoms persist would subsequently re-attend and be referred.
Having identified a sequential testing strategy on clinical evidence, the health economic
modelling unequivocally identified that serum CA125 was the most cost-effective first test
as opposed to ultrasound or ultrasound and serum CA125 in combination.
It was recognised that there would be an impact on health service resources and women
tested due to the low prevalence of ovarian cancer in the symptomatic patient group.
Equally, it was felt that in order to ensure symptomatic women were placed along the
correct pathway as soon as possible it could only be achieved using such a sequential
testing strategy.
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27
3 Establishing the diagnosis

in secondary care
The objectives of this chapter were:

1. to estimate the sensitivity, specificity and positive/negative predictive values of
serum tumour markers (other than serum CA125) in women with suspected ovarian
cancer
2. to determine which malignancy index is the more accurate in assessing the
probability of malignant pathology in women with suspected ovarian cancer
3. to determine which imaging tests should be done in women with suspected
ovarian cancer
4. to determine when it is appropriate for women with suspected advanced ovarian
cancer not to have a tissue diagnosis before starting chemotherapy
5. to determine whether samples from image-guided biopsy or laparoscopic biopsy
are the best method of tissue diagnosis before chemotherapy.
3.1

Tumour markers are a group of proteins, hormones, enzymes, receptors, and other cellular
products that are over-expressed by malignant cells. The evidence supporting the use of
serum CA125 as a useful predictive tumour marker in suspected ovarian cancer is strong
(see clinical evidence in section 2.2). It is raised in 90% of such women but can also be
significantly elevated in other benign and malignant conditions.
This review of clinical evidence sought to look at individual tumour markers in addition to
serum CA125, especially ones which had been developed more recently, to see if any of
these might facilitate the diagnosis in women with suspected ovarian cancer, if routinely
carried out. These included CEA, CDX2, CA 72-4, CA 19-9, AFP, beta-hCG and HE4.
Clinical question: For women with suspected ovarian cancer, what serum
tumour marker tests should be routinely carried out to aid in diagnosis?
Clinical evidence
The evidence review considered the diagnostic accuracy of the following serum tumour
markers CEA, CDX2, CA 72-4, CA 19-9, AFP, beta-hCG and HE4 in comparison to serum
CA125 in women with suspected ovarian cancer. The evidence came from 39 studies of
women who had surgery for pelvic tumours with histopathology to confirm their
diagnosis. This means that the evidence is not directly applicable to women with
symptoms of ovarian cancer in primary care.
The overall methodological quality of these studies was moderate to low most were
case series and not designed as prospective diagnostic studies. The reference standard
diagnosis (histopathology) was consistently applied but the timing of the serum tumour
marker tests and the use of blinding in the interpretation of tests were rarely reported.
28
HE4
There was consistent evidence, from five studies comparing HE4 and serum CA125 in
women with pelvic masses, that HE4 is more sensitive and specific than serum CA125 for
the diagnosis of ovarian cancer (Abdel-Azeez et al., 2010; Huhtinen et al., 2009; Moore
et al., 2008; Nolen et al., 2010; Shah et al., 2009). These five studies included a total of
434 women with ovarian cancer and 583 with benign disease.
Summary ROC curves suggested peak sensitivity/specificity of 77% for serum CA125
compared with 83% for HE4. From these figures, for every 1,000 women referred for
diagnosis of a pelvic tumour, using HE4 instead of serum CA125 would identify an
additional seven patients with cancer with 81 fewer false positives (assuming a 10%
prevalence of undiagnosed ovarian cancer in this population (Myers et al., 2006)).
Five studies looked at the combination of HE4 and serum CA125 (Abdel-Azeez et al.,
2010; Huhtinen et al., 2009; Moore et al., 2008; Moore et al., 2009; Nolen et al., 2010).
The evidence suggests that the combination of HE4 and serum CA125 is more specific,
but less sensitive than either marker in isolation.
CA 72.4
Ten studies, including 933 women with ovarian cancer and 1,300 with benign disease,
compared CA 72.4 to serum CA125. The pooled results suggested CA 72.4 and serum
CA125 have similar peak sensitivity/specificity, 78% and 77% respectively. It is clear
from the ROC curves, however, that (at least at the diagnostic thresholds used in the
studies) CA 72.4 has a lower sensitivity and higher specificity than serum CA125.
Evidence from a further six studies suggests that combining the two markers could
increase their specificity, but at the cost of sensitivity.
CA 19.9
Eight studies including 576 women with malignant tumours and 1,432 with benign
disease, compared the diagnostic accuracy of CA 19-9 and serum CA125 in women with
pelvic masses.The summary ROC curve suggests CA 19.9 has relatively low sensitivity for
the diagnosis of ovarian cancer, at the diagnostic thresholds used in the studies.
CEA, CDX2, AFP and beta-hCG

Eight studies including 1,172 women, reported the diagnostic accuracy of CEA for the
diagnosis of ovarian cancer in women with suspected ovarian cancer. Serum CEA was
raised in approximately 26% of women with ovarian cancer (sensitivity 26%), but
specificity varied widely between studies.
The literature searches found no studies about the use of the marker CDX2. There was a
single study each about the use of serum beta-hCG and serum AFP in the diagnosis of
ovarian cancer, suggesting low sensitivity for these markers. AFP and hCG are important
markers for triage.
Multiple tumour marker panels

Three of the studies (Nolen et al., 2010; Moore et al., 2008; Abel-Azeez et al., 2010)
investigated panels combining three or more serum tumour markers. There was no
evidence to suggest that multiple tumour markers were much better than the two marker
combination of serum CA125 and HE4.
29
Recommendations
Measure serum CA125 in secondary care in all women with suspected ovarian
cancer, if this has not already been done in primary care.
In women under 40 with suspected ovarian cancer, measure levels of alpha
fetoprotein (AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as
serum CA125, to identify women who may not have epithelial ovarian cancer.

The GDG placed a high value on the outcomes of sensitivity and specificity of the
different tumour marker tests for facilitating a diagnosis of ovarian cancer. At this time
there is ample evidence supporting the clinical utility of serum CA125 in diagnosing
ovarian cancer. The GDG acknowledged that the methodological quality of the evidence
was low, with most studies being case series and not designed as prospective diagnostic
or prognostic studies.
The GDG noted that although the preliminary data on HE4 showed it to have a relatively
high sensitivity and specificity, it was not in routine clinical use and studies about its
diagnostic performance had only recently been published. The GDG therefore did not
feel the data on HE4 was substantial enough to enable it to be recommended instead of
serum CA125 the only serum tumour marker with widely accepted clinical utility in
women with ovarian cancer. They therefore recommended the routine use of serum
CA125.
This clinical question was agreed as a medium priority for health economic evaluation
because although there are potential cost differences between the different combinations
of serum tumour markers used, other clinical questions were considered higher priority
for investigation.
3.2
Malignancy indices
In women with an adnexal mass it is important to distinguish between benign and
malignant pathology before surgical treatment. Improving outcomes in gynaecological
cancers guidance (Department of Health, 1999) recommends that women with ovarian
cancer be discussed at a multidisciplinary team meeting and be offered, where appropriate,
a laparotomy, a full staging procedure and optimal debulking in a cancer centre by a
trained gynaecological oncologist. In contrast, women with low or moderate risk of ovarian
cancer can be managed by gynaecological cancer leads in a cancer unit. At present,
several parameters are available to help distinguish between benign and malignant masses.
These include menopausal status or age, ultrasound characteristics with or without Doppler
flow assessment and tumour markers such as serum CA125. These parameters can be
combined to provide risk of malignancy indices that can help to predict the probability of
malignancy. At present, none of the currently available tests can provide 100% sensitivity
or specificity; however, most of the available prediction models are useful in the preoperative assessment of the adnexal mass.
30
Clinical question: For women with suspected ovarian cancer, which malignancy
index is the most effective?
Clinical evidence
The evidence for this topic comprised one good quality systematic review of diagnostic
studies (Geomini et al., 2009) in which the reviewers appraised 109 studies of eightythree validated risk of malignancy models. By pooling data appropriately the authors
concluded that the RMI I proposed by Jacobs et al., (1990) was superior in terms of
sensitivity and specificity to the other comparators. With a cut-off score of 200, sensitivity
= 78% [95%CI: 71-85%] and specificity = 87% [95%CI: 83-91%] and with a cut-off
score of 50, sensitivity = 91% [95%CI: 85-97%] and specificity = 74% [95%CI: 69-80%].
Raza et al., (2010) published a rapid communication reporting the results of a
prospective observational study that had been conducted in a UK hospital. Using Jacobs
RMI I, as modified by Tingulstad et al., (1996) they referred all women with a suspicious
mass and a score of 450 directly to the cancer clinic. All patients were first discussed at
a MDT meeting and those with a lower RMI score may still have been referred if there
were clinical indications of malignancy. Of 104 women in the study, 27 were directly
referred, of which one had benign disease. One woman with a low RMI was referred to
the clinic on the basis of having had a suspicious CT scan. With a cut-off score in this
very limited population, the RMI I index had sensitivity = 96.2% [95%CI: 80.4-99%] and
specificity 98.7% [95%CI: 93.1-100%].
Recommendation
Calculate a risk of malignancy index I (RMI I) score1 (after performing an ultrasound;
see section 3.3 on page 32) and refer all women with an RMI I score of 250 or
greater to a specialist multidisciplinary team.

The GDG noted that there was high-quality evidence that RMI I was the most useful
index at identifying women with ovarian cancer compared to other malignancy indices,
but only in the secondary care setting. However the GDG recognised that although the
evidence showed RMI I to be the more useful index, it did not indicate the optimum cutoff score to use for guiding management.
The GDG felt that an RMI I cut-off of 250 should be used because this would ensure
access to specialist centres whilst not overburdening them with benign disease (and the
additional costs associated with this).
It was also noted that the value of the cut-off score used, affected the sensitivity of RMI I
relative to the specificity. For example, a low cut-off score could mean that some women
who did not have ovarian cancer would be wrongly identified as positive and referred for
specialist treatment. Conversely, a high cut-off score could mean that some women who
did have ovarian cancer would not be identified or referred for specialist treatment.
The GDG agreed that this clinical question was not relevant for health economic
evaluation because it is unlikely that the different malignancy indices would have a
direct impact on patient outcomes.
1
31
Box 3.1 Risk of malignancy index RMI I2

RMI I combines three pre-surgical features: serum CA125 (CA125), menopausal status (M) and
ultrasound score (U). The RMI is a product of the ultrasound scan score, the menopausal
status and the serum CA125 level (IU/ml).
RMI = U x M x CA125
The ultrasound result is scored 1 point for each of the following characteristics:
multilocular cysts, solid areas, metastases, ascites and bilateral lesions. U=0 (for an
ultrasound score of 0), U=1 (for an ultrasound score of 1), U=3 (for an ultrasound score
of 2-5).
The menopausal status is scored as 1= pre-menopausal and 3 = post-menopausal
The classification of post-menopausal is women who have had no period for more
than one year or women over the age of 50 who have had a hysterectomy.
Serum CA125 is measured in IU/ml and can vary between 0 to hundreds or even
thousands of units.
Further research should be undertaken to determine the optimum RMI I threshold
that should be applied in secondary care to guide the management of women with
suspected ovarian cancer.
3.3

Imaging is used to characterise the extent and spread of ovarian cancer. This information
can be used for staging and influencing management decisions. In addition it may facilitate
image-guided biopsy to enable histological confirmation of diagnosis. Appropriate imaging
will also allow a baseline to be established in order that later imaging can assess response
to chemotherapy, or assess disease relapse.
The principal imaging modalities comprise ultrasound, computerised tomography (CT)
scans and magnetic resonance imaging (MRI), all of which have the capacity to
characterise adnexal masses and to assess extent of spread and operability. In addition to
how well a test functions one should consider other issues such as availability, cost, and
safety.
Ultrasound has the advantage of being more available, cheaper and safer. Grey-scale
ultrasound performs well in identifying simple cystic masses that have a high negative
predictive value. It is therefore well placed as an initial test and enables adnexal masses to
be triaged into low (not ovarian cancer) and higher risk (suspected ovarian cancer)
categories.
Women with ovarian cancer can often have associated pleural effusions, which if
malignant, have significant staging and possible management implications. CT is the
investigation of choice for detection of disease in the thorax.
MRI is established as a tool for characterisation of pelvic masses because of its ability to
discriminate masses that contain both fat and blood, neither of which are features of
malignancy. However, MRI is less available, scan times are much longer, and imaging of
the abdomen can be degraded by movement caused by breathing which may affect the
sensitivity of detection of omental and peritoneal disease.
Jacobs I, Oram D, Fairbanks J, Turner J, Frost C and Grudzinskas JG (1990) A risk of malignancy index incorporating CA125,
ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol, 97: 922-929.
32
In higher risk women, further assessment of extent of spread is required to aid management
in terms of identifying sites for biopsy and consideration for surgery. A CT scan has the
advantage of enabling a more comprehensive assessment of the body, and is superior to
MRI and ultrasound for assessment of the sub-diaphragmatic regions, gastro-splenic
ligament, lesser sac and retroperitoneal nodal disease; sites of likely spread of ovarian
cancer. CT is less operator dependent than ultrasound, and more available than MRI.
Finally CT also provides optimal baseline information in order to assess response to
chemotherapy and disease relapse.
Clinical question: For women with suspected ovarian cancer, what is the most
appropriate imaging to be done to determine future management?
Clinical evidence
Differentiation of benign from malignant ovarian tumours
Evidence from good quality diagnostic systematic reviews and meta-analysis (Liu et al.,
2007, Kinkel et al., 2000; Kinkel et al., 2005; Medeiros et al., 2009; Myers et al., 2006)
suggests the accuracy of combined grey-scale/colour Doppler ultrasound, CT and MRI for
the differentiation of benign and malignant ovarian masses, are broadly similar, with
sensitivity approaching 90% and specificity exceeding 85%.
Li et al., (2007) note that ultrasound is most accurate in identifying simple cystic masses,
and the ultrasound studies in their meta-analysis had a lower prevalence of complex
ovarian lesions than the CT and MRI studies. It is possible that the diagnostic utility of
MRI and CT is underestimated in the meta-analyses. Kinkel et al., (2005) reviewed
evidence for imaging in women with indeterminate masses at grey-scale ultrasound,
presumably excluding those women with simple cystic masses. In this group of patients
MRI had a higher positive predictive value (post-test probability), than CT and combined
grey-scale/colour Doppler ultrasound.
Staging
There was limited evidence about the optimal imaging modality for staging. A
prospective multicentre study including 280 women (Tempany et al., 2000) concluded
that CT and MRI were more accurate than ultrasound for staging ovarian cancer.
Prediction of optimal cytoreduction

Most of the evidence about the prediction of optimal cytoreduction came from studies
using CT (Bristow et al., 2000; Byrom et al., 2002 Dowdy et al., 2004; Ferrandina et al.,
2009; Forstner et al., 1995; Gemer et al., 2009; Meyer et al., 1995; Nelson et al., 1993;
Kebapci et al., 2010; Jung et al., 2010; Qayyum et al., 2004) with only one ultrasound
study (Testa et al., 2006) and two MRI studies (Forstner et al., 1995; Qayyum et al.,
2005).
Five studies (Nelson et al., 1993; Bristow et al., 2000; Dowdy et al., 2004; Quayyum
et al., 2004; Meyer et al., 1995) reported models to predict suboptimal cytoreduction on
the basis of CT features.
Although the authors of these models report reasonable sensitivity and specificity for their
models, two independent studies (Axtell et al., 2007; Gemer et al., 2009) did not validate
these findings. The low positive predictive values reported by Axtell et al., (2007) and
Gemer et al., (2009) suggest that most patients predicted to have sub-optimal
cytoreduction will in fact be optimally cytoreduced at operation.
33
Recommendations
Perform an ultrasound of the abdomen and pelvis as the first imaging test in
secondary care for women with suspected ovarian cancer, if this has not already
been done in primary care.
If the ultrasound, serum CA125 and clinical status suggest ovarian cancer,
perform a CT scan of the pelvis and abdomen to establish the extent of disease.
Include the thorax if clinically indicated.
Do not use MRI routinely for assessing women with suspected ovarian cancer.

The GDG placed a high value on the need to establish a diagnosis of ovarian cancer and
to determine the extent of disease to inform multidisciplinary team discussions.
There was good quality evidence from systematic reviews on which to base the
recommendations on diagnosis. The GDG agreed that the sensitivity and specificity of
ultrasound and CT for establishing a diagnosis, were shown to be broadly equivalent, but
that the evidence did not specify which of these imaging modalities was the most
effective. Given that ultrasound and CT had been shown to have equivalent sensitivity
and specificity, and that ultrasound is more readily available, less costly and involves no
radiation unlike CT, the GDG felt it was appropriate to recommend ultrasound as the
initial imaging test for women with suspected ovarian cancer.
The GDG noted that the evidence for the staging of ovarian cancer was sparse. The GDG
recognised that ultrasound is subjective and operator dependent and has limitations in
detecting peritoneal disease, whereas multi-slice CT has high spatial resolution and is
more sensitive for assessment of omental and peritoneal disease, and abdominal and
pelvic lymph nodes. CT is the investigation of choice for staging thoracic disease. For
these reasons the GDG chose CT to be the investigation of choice for staging.
MRI is less specific for establishing the extent of disease, it is less available and takes
longer than CT or ultrasound. For these reasons the GDG were unable to recommend
MRI for routine use.
This clinical question was considered as a medium priority for health economic
evaluation because the population involved was relatively small and the cost difference
between the competing alternatives was minimal.
Recommendations
Large multicentre casecontrol studies should be conducted to compare the
accuracy of CT versus MRI for staging and for predicting optimal cytoreduction in
women with ovarian cancer.
3.4
Tissue diagnosis
Requirement for tissue diagnosis
Without a tissue diagnosis there is always a degree of diagnostic uncertainty. In most
instances, histology is the only way of determining the cancer type and grade and will also
exclude other diagnoses such as tuberculosis, inflammation, fibrosis and other infections.
Different histological types of ovarian cancer require different treatments, and so confirmed
histological diagnosis is considered important.
34
Histological diagnosis is usually made following surgery. In some cases, for example where
surgery is not feasible or where chemotherapy is the initial treatment, other options for
obtaining a histological diagnosis may be considered.
There are a range of methods of obtaining a tissue diagnosis including needle biopsy,
laparoscopy or open laparotomy. All are invasive and therefore carry risks. In addition,
attempts at tissue diagnosis are not always successful and this may delay the start of
treatment. Another method of obtaining a tissue diagnosis is the use of frozen section at the
time of surgery. However, this suffers from sampling error and is not widely practised in the
UK.
Cytology (examination of individual cells aspirated from intra-abdominal fluid or rarely
from a tumour) is generally safer than tissue biopsy but has a lower diagnostic accuracy.
When it is hazardous or difficult to obtain a tissue diagnosis, the risks of such procedures
need to be weighed against the potential benefits of greater diagnostic accuracy. After
discussion with the woman it may be concluded that a tissue diagnosis is not essential.
Clinical question: For women with suspected advanced ovarian cancer, when is
it appropriate not to have a tissue diagnosis before starting chemotherapy?
Clinical evidence
There were no studies comparing the outcomes of women with suspected versus
confirmed advanced ovarian cancer treated with chemotherapy. Evidence from case
series suggests a minority of women (45%) with presumed advanced ovarian cancer on
the basis of clinical and imaging findings will not have ovarian cancer (Griffin et al.,
2009; Freedman et al., 2010). Thus if tissue diagnosis were omitted some women might
receive inappropriate treatment.
Cytomorphology combined with immunocytochemistry had a rate of definitive diagnosis
of primary tumour site in malignant effusions ranging from 57% to 87% (Mottolese et al.,
1988; Pomjanski et al., 2005; Longatto-Filho et al., 1997; DiBonito et al,. 1993). In
comparison, histopathology plus immunohistochemistry had a diagnostic rate between
87% and 97% in women with peritoneal carcinomatosis of unknown origin (Hewitt
et al., 2006; Spencer et al., 2001) or presumed advanced ovarian cancer (Griffin et al.,
2009).
There were no data about complications of effusion cytology. Percutaneous core biopsy
was associated with minor local bruising and discomfort (Fisherova et al., 2008; Griffin et
al., 2009; Hewitt et al., 2006; Pombo et al., 1997; Spencer et al., 2001). There was no
direct evidence about the harms of diagnostic laparoscopy or laparotomy in women with
suspected advanced ovarian cancer due to receive chemotherapy. Indirect evidence
comes from studies reporting diagnostic laparoscopy in patients with ascites of unknown
origin (Bedioui et al., 2007; Chu et al., 1994; Yoon et al., 2007). Minor complications
were reported in less than two percent of laparoscopies. Major complications occurred at
a rate of less than one percent.
35
Recommendations
If offering cytotoxic chemotherapy to women with suspected advanced ovarian
cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if
histology is not appropriate) in all but exceptional cases.
Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without a
tissue diagnosis (histology or cytology) only:
in exceptional cases, after discussion at the multidisciplinary team and

after discussing with the woman the possible benefits and risks of starting
chemotherapy without a tissue diagnosis.

The GDG noted that the evidence for this clinical question consisted of small
retrospective studies of moderate quality.
The GDG felt that having a tissue diagnosis was essential to guiding future treatment, but
recognised that on occasions the risks of obtaining a histological diagnosis might not be
justified. In these circumstances, the use of cytological diagnosis alone will suffice but
the risk of giving chemotherapy when the diagnosis might be uncertain has to be
weighed against the potential risks of obtaining histological confirmation.
This clinical question was agreed as a low priority for health economic evaluation
because of the lack of good quality prospective clinical studies in this area.
Methods of tissue diagnosis other than laparotomy

Image-guided biopsy is usually performed under local anaesthetic in the radiology
department using ultrasound or CT to sample an accessible area of abnormality such as a
peritoneal deposit or omental disease. The biopsy needle is inserted percutaneously and
several passes are usually made to obtain thin tissue cores. This technique is not suitable
for all women, for example if the disease is not in an accessible location. It is associated
with minor complications, such as local bruising and discomfort. Targeting of the
abnormality for biopsy is limited by the imaging technique used and the samples are much
smaller, reducing the diagnostic yield. This potentially results in a lower success rate
requiring a repeat procedure or surgical biopsy.
When image-guided biopsy is not appropriate or if the procedure has failed to obtain an
adequate sample, a secondary intervention may be required to obtain tissue for diagnosis.
Laparoscopy is a surgical technique that uses an endoscope that gives a complete view but
full visualisation of the peritoneal cavity and allows a biopsy to be performed. It requires a
general anaesthetic and is more complex to perform. Laparoscopy is associated with both
major and minor complications, with higher associated major complication rates than
image-guided biopsy.
Both techniques have the potential to damage the abdomino-pelvic organs which may be
displaced or tethered to abnormal positions by tumour, fibrosis or inflammation. There is
also a potential risk of tumour being deposited along the biopsy needle track or implanted
into the laparoscopic surgery sites.
36
Clinical question: What is the best method of tissue diagnosis before

chemotherapy, samples from image-guided biopsy or laparoscopic biopsy?
Clinical evidence
The literature search found no studies directly comparing image-guided with
laparoscopic biopsy. Evidence from case series indicates a definitive diagnostic rate
between 87% and 97% for image-guided biopsy (Griffin et al., 2009; Hewitt et al., 2006;
Spencer et al., 2001), but our searches found no studies reporting the diagnostic yield of
laparoscopic biopsy.
Percutaneous core biopsy was associated with minor local bruising and discomfort
(Griffin et al., 2009; Hewitt et al., 2006; Spencer et al., 2001). Minor complications were
reported in less than two percent of laparoscopies from three series (Dedioui et al., 2007,
Chu et al., 1994; Yoon et al., 2007) with 1,284 patients (including cases with nonmalignant aetiology). Major complications occurred at a rate of less than one percent.
Recommendations
If surgery has not been performed, use histology rather than cytology to obtain a
tissue diagnosis. To obtain tissue for histology:
use percutaneous image-guided biopsy if this is feasible
consider laparoscopic biopsy if percutaneous image-guided biopsy is not
feasible or has not produced an adequate sample.
Use cytology if histology is not appropriate.

There was low quality evidence, with no studies directly comparing image-guided biopsy
with laparoscopic biopsy, and so case series evidence for the risks and accuracy of each
technique in isolation was reviewed.
The GDG acknowledged that although there was evidence for the diagnostic yield of
image-guided biopsy there was none reporting the diagnostic yield of laparoscopic
biopsy. They also noted that higher associated major complication rates were reported
with laparoscopic biopsy than image-guided biopsy. The GDG therefore put a high value
on the outcomes of morbidity and adverse events associated with the two techniques,
and agreed that the simplest and least invasive technique was image-guided biopsy.
This clinical question was originally agreed a high priority for health economic
evaluation because the number of patients involved could potentially be large and there
could be significant cost implications. Due to the lack of comparative clinical evidence,
which would hinder the development of a robust economic analysis it was reconsidered
as a low priority. Economic evaluation based on poor quality data would carry a high
level of uncertainty and potentially limit its usefulness in informing recommendations.
37
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cytoreduction in epithelial ovarian carcinoma J.Clin.Oncol. 11: 166-172.
Nolen B, Velikokhatnaya L, Marrangoni A, De GK, Lomakin A, Bast RC, Jr. and Lokshin A (2010). Serum biomarker panels for the
discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol.Oncol. 117: 440-445.
Pombo F, Rodriguez E, Martin R and Lago M (1997) CT-guided core-needle biopsy in omental pathology Acta Radiol. 38:
978-981.
Pomjanski N, Grote HJ, Doganay P, Schmiemann V, Buckstegge B, Bocking A. (2005) Immunocytochemical identification of
carcinomas of unknown primary in serous effusions. Diagnostic Cytopathology. 33(5): 309-15.
Qayyum A, Coakley FV, Westphalen AC, Hricak H, Okuno WT and Powell B (2005) Role of CT and MR imaging in predicting
optimal cytoreduction of newly diagnosed primary epithelial ovarian cancer Gynecol.Oncol. 96: 301-306.
Raza A, Mould T, Wilson M, Burnell M, Bernhardt L. (2010) Increasing the effectiveness of referral of ovarian masses from cancer
unit to cancer center by using a higher referral value of the risk of malignancy index. Int J Gynecol Cancer 20(4): 552-554.
Shah CA, Lowe KA, Paley P, Wallace E, Anderson GL, McIntosh MW, et al. (2009) Influence of ovarian cancer risk status on the
diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125. Cancer Epidemiology, Biomarkers & Prevention
18(5): 1365-72.
Spencer JA, Swift SE, Wilkinson N, Boon AP, Lane G and Perren TJ (2001) Peritoneal carcinomatosis: Image-guided peritoneal core
biopsy for tumor type and patient care Radiology 221: 173-177.
Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. (2008) National Academy of Clinical Biochemistry
laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.
Clin Chem 54(12): e11-79.
Tempany CM, Zou KH, Silverman SG, Brown DL, Kurtz AB and McNeil BJ (2000) Staging of advanced ovarian cancer: comparison
of imaging modalitiesreport from the Radiological Diagnostic Oncology Group Radiology 215: 761-767.
Testa AC, Ludovisi M, Savelli L, Fruscella E, Ghi T, Fagotti A, Scambia G and Ferrandina G (2006) Ultrasound and color power
Doppler in the detection of metastatic omentum: a prospective study Ultrasound in Obstetrics & Gynecology 27: 65-70.
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gastroenterology unit? J Gastroenterol 42(11): 881-6.
39
4 Management of suspected
early (stage I) ovarian
cancer

1. to determine whether the systematic removal of the retroperitoneal lymph nodes during
surgical treatment for suspected early stage ovarian cancer confers any added benefit as
opposed to conventional surgical staging which includes lymph node sampling.
2. to determine the clinical benefits and toxicity of first-line adjuvant chemotherapy for
women with stage I ovarian cancer.
4.1

In women whose disease is thought to be confined to the ovary(s), optimum surgical
staging comprises midline laparotomy to allow thorough assessment of the abdomen and
pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic
omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and
abdominal peritoneum and retroperitoneal lymph node assessment (Winter-Roach et al.,
2009). In women where the disease appears to be confined to one ovary and who wish to
conserve fertility, then conservative surgery can be considered where the uterus and
contra-lateral ovary are conserved.
It is recognised that around 22% of women considered to have stage I ovarian cancer, will
in fact have occult retroperitoneal lymph node metastases which can only be identified by
removing affected nodes (Maggioni et al., 2006). Current surgical staging guidelines
advocate only sampling a number of pelvic and/or para-aortic nodes but inevitably less will
be sampled than in a systematic retroperitoneal lymphadenectomy, which aims to remove
all pelvic and para-aortic lymph nodes up to the renal vessels as a block dissection on both
sides. Removing all affected nodes will improve staging and might be therapeutic.
Systematic retroperitoneal lymphadenectomy is a major surgical procedure which carries
the potential risks of prolonged anaesthesia and surgical complications such as increased
blood loss and transfusion, ureteric injury, lymphoedema, lymphocysts, damage to nerves
and major vessels. In addition to concerns about morbidity, there are resource implications.
The use of peri-operative frozen section to confirm malignancy has been proposed. This
might be a way of selecting only those patients with ovarian cancer for systematic
retroperitoneal lymphadenectomy, thereby reducing the risks and costs of this strategy.
There is, however, no international agreement on whether the potential survival benefits of
systematic retroperitoneal lymphadenectomy outweigh the risks.
40
Clinical question: For women with ovarian cancer whose disease appears
confined to the ovaries, what is the effectiveness of systematic retroperitoneal
lymphadenectomy in surgical management?
Clinical evidence
The evidence for this topic was generally of low quality, comprising two retrospective
observational studies, one non-randomised comparative study and a small randomised
controlled trial (RCT) (Table 4.1). Across all studies, the majority of women had stage I
ovarian cancer. Only the RCT reported the incidence of post-surgical morbidity and none
of the papers reported on patient quality of life. The results of survival outcomes were
inconsistent between studies.
Maggioni et al., (2006) presented results from a small, underpowered study that was
unable to demonstrate a difference in short or long term survival between patients having
surgery alone or surgery with systematic lymphadenectomy (SL). But the more extensive
operation was associated with increased morbidity. Conversely, Yokoyama et al., (1999)
found a significant difference in the rates of 5 and 10 year survival for women with stage
I/II disease who had received SL compared with those who had not (100% vs. 71.4%
(P<0.05) and 83.9% vs. 61.1% (P<0.05) respectively). These results may have been
confounded by the addition of different chemotherapy regimens to the study arms.
The retrospective studies also reported conflicting results for survival. The largest study
(Chan et al., 2007; N=6,686) found a significant improvement in the rate of 5 year
disease-specific survival for women who underwent SL as part of staging compared with
women who did not (92.6% 0.6 vs. 87% 0.6 P<0.001). However, during the study
period participants had unrecorded treatments including surgery and/or chemotherapy
which could have confounded these results. The smaller study (Yang et al., 2007) found
no significant differences in survival after 1, 3, 5 or 10 years between women that had
undergone SL after primary surgery and those who had not. Again, some participants had
subsequently received chemotherapy which could have confounded the results.
Kim et al., (2010) conducted a thorough systematic review and meta-analysis of RCTs
and observational studies to determine the possible benefit of systematic retroperitoneal
lymphadenectomy to women with all stages of ovarian cancer. A sub-set of patients had
stage I-II disease and these data showed a survival advantage with SL (HR: 0.80 [95%CI:
0.70-0.92] (P=0.001) with no between studies heterogeneity. However, the included
studies were not of high evidential quality consisting of Chan et al., 2007; Maggioni
et al., 2006 and a small retrospective observational study (Suzuki et al., 2008).
41
42
Design
Limitations
Inconsistency
Indirectness
retrospective
observational
study
N/A
N/A
N/A
N/A
N/A
Imprecision
retrospective
observational
study
N/A
N/A
N/A
retrospective
observational
study
N/A
N/A
retrospective
observational
study
N/A
N/A
retrospective
observational
study
N/A
N/A
retrospective
observational
study
N/A
N/A
N/A
N/A
N/A
N/A
retrospective
observational
study
N/A
N/A
N/A
5 year disease-specific survival. Grade 3 disease (P<0.001) Chan et al. (2007).
5 year disease-specific survival. Stage I disease (P<0.001) Chan et al. (2006).
5 year disease-specific survival. No surgery (P=0.02) Chan et al. (2007).
5 year disease-specific survival. Hysterectomy (P=0.01) Chan et al. (2007).
5 year disease-specific survival. No hysterectomy (P<0.001) Chan et al. (2007).
N/A
N/A
N/A
N/A
N/A
N/A
5 year disease-specific survival. Non-clear cell epithelial carcinoma (P<0.001) Chan et al. (2007).
5 year disease-specific survival. Age >50 years (P<0.001) Chan et al. (2007).
5 year disease-specific survival. All study participants (P<0.001) Chan et al. (2007).
retrospective
1
N/A
N/A
N/A
observational study
No of
studies
Quality
nil
nil
nil
nil
nil
nil
nil
nil
Other
631
845
2,253
603
2,136
1,562
2,862
Patients
with SL
633
995
242
2,342
1,240
2,900
2,360
3,824
Patients
with no SL
88.8 1.6
88.1 1.4
100 0.0
91.5 0.5
96.5 0.9
93.3 0.7
92 0.9
92.6 0.6
% survived
SL
74.4 2.0
72.8 1.6
32.9 4.2
88.3 0.7
92.0 0.9
85.9 0.9
82.3 0.9
87 0.6
% survived
no SL
Summary of findings
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
Quality
Table 4.1 GRADE profile: For women with ovarian cancer whose disease appears confined to the ovaries, what is the effectiveness of systematic retroperitoneal
lymphadenectomy in surgical management?
Design
Limitations
Inconsistency
Quality
Indirectness
retrospective
observational
study
N/A
N/A
N/A
retrospective
observational
study
N/A
retrospective
observational
study
N/A
retrospective
observational
study
N/A
retrospective
observational
study
N/A
retrospective
observational
study
N/A
retrospective
observational
study
N/A
retrospective
observational
study
N/A
3 year survival stage II (% only) Yang et al. (2007)
10 year survival stage I (% only) Yang et al. (2007)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
5 year disease-specific survival. Caucasian race (P<0.001) Chan et al. (2007).
5 year disease-specific survival. No radiation therapy (P<0.001) Chan et al. (2007).
No of
studies
Table 4.1 (Cont.)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Imprecision
nil
nil
nil
nil
nil
nil
nil
nil
Other
22
22
33
33
33
33
2,166
2,758
Patients
with SL
11
11
18
18
18
18
2,906
3,722
Patients
with no SL
76.5
87.2
82.1
83.5
92.3
99.4
92.9 0.7
92.9 0.6
% survived
SL
74.6
86.3
81.0
82.7
91.9
97.5
86.1 0.7
87.1 0.6
% survived
no SL
Summary of findings
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
Quality
43
44
Design
Limitations
retrospective
observational
study
N/A
retrospective
observational
study
N/A
N/A
N/A
Inconsistency
Quality
non-randomised
comparative study
N/A
N/A
non-randomised
comparative study
N/A
N/A
randomised
controlled trial
no serious
limitations
N/A
randomised
controlled trial
no serious
limitations
randomised
controlled trial
no serious
limitations
5 year overall survival Maggioni et al. (2006)
N/A
N/A
Risk of progression All participants (P>0.05) Maggioni et al. (2006)
Risk of death. All participants (P>0.05) Maggioni et al. (2006)
Estimated 10 year survival for stages I and II (% only) Yokoyama et al. (1999)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Indirectness
Estimated 5 year survival for stages I and II (% only) Yokoyama et al. (1999)
No of studies
Table 4.1 (Cont.)
underpowered
study
underpowered
study
underpowered
study
N/A
N/A
N/A
N/A
Imprecision
N/A
N/A
N/A
nil
nil
nil
nil
Other
84%
138
138
80
80
22
22
81.6%
130
130
75
75
11
11
MD=2.4
(-8.3-8.9)
HR=0.72
(0.46-1.14)
HR=0.85
(0.49-1.47)
83.9
100
54.3
68.9
Patients with Patients with % survived

SL
no SL
SL
61.1
71.4
50.6
65.4
% survived
no SL
Summary of findings
LOW
LOW
LOW
VERY LOW
VERY LOW
VERY LOW
VERY LOW
Quality
Design
Limitations
randomised
controlled trial
serious
limitations1
no serious
limitations
no serious
inconsistency
N/A
Inconsistency
Quality
no serious
indirectness
N/A
Indirectness
no serious
imprecision
underpowered
study
Imprecision
N/A
N/A
Other
78.3%
73.4%
HR=0.80
(0.70-0.92)
MD=4.9
(-5.9-12.5)
Patients with Patients with % survived

SL
no SL
SL
% survived
no SL
Summary of findings
MODERATE
LOW
Quality
This study combined one small RCT and two observational studies which showed no between studies heterogeneity (0%) and gave a significant result. Nonetheless, the included studies were
themselves between low and moderate quality.
randomised
trial and
observational
studies
Overall survival. Kim et al., (2010)1
5 year progression-free survival Maggioni et al. (2006)
No of studies
Table 4.1 (Cont.)
45
Recommendation
Perform retroperitoneal lymph node assessment1 as part of optimal surgical staging2 in
women with suspected ovarian cancer whose disease appears to be confined to the ovaries
(that is, who appear to have stage I disease)
Do not include systematic retroperitoneal lymphadenectomy (block dissection of lymph

nodes from the pelvic side walls to the level of the renal veins) as part of standard surgical
treatment in women with suspected ovarian cancer whose disease appears to be confined
to the ovaries (that is, who appear to have stage I disease).

The GDG acknowledged that evidence on the basis of study quality assessed according
to GRADE was limited and of poor quality. There was no demonstrable survival benefit
from systematic retroperitoneal lymphadenectomy compared to lymph node sampling.
They also noted that no studies reported on quality of life.
The GDG reaffirm the need for accurate staging, particularly in women with suspected
early ovarian cancer, but were not convinced that the greater risks and costs of
systematic retroperitoneal lymphadenectomy compared to conventional lymph node
sampling were justifiable. Therefore they were unable to recommend its use in women
whose disease appears to be confined to the ovaries.
This clinical question was agreed as a low priority for health economic evaluation
because of the lack of good quality RCT data in this area. Also, given that an economic
evaluation would be unlikely to clarify the uncertain health benefits associated with
these interventions, the added value of such an analysis was lower than for other clinical
questions.
A prospective randomised trial should be undertaken to evaluate the therapeutic effect,
associated risks and cost effectiveness of systematic retroperitoneal lymphadenectomy in
women with ovarian cancer whose disease appears to be confined to the ovaries.
4.2

No surgical staging procedure is perfect and in a proportion of women in whom the disease
is thought to be confined to the ovaries and completely removed at operation there may, in
fact, be occult residual disease.
In women with apparent stage I disease, chemotherapy can be given in certain
circumstances, such as poorly differentiated tumours and in certain histological sub-types
(for example, clear cell carcinomas). This is done to treat residual disease that is suspected
but may not, in fact, exist. Therefore some women without residual disease will receive
chemotherapy with its associated risks.
12
1
Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if
there is a palpable abnormality, or random sampling if there is no palpable abnormality.
2
Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total
random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment [Winter Roach BA,
Database of Systematic Reviews issue 3: CD004706].
46
Given that women with stage I ovarian cancer have significantly less disease it is possible
that less chemotherapy will be required for cure. Currently NICE technology appraisal
guidance 55 (NICE, 2003) recommends a choice of either platinum based compound on its
own or in combination with paclitaxel (see section 5.3) but does not stipulate the number
of cycles to be given. It is logical that reducing the number of cycles of chemotherapy is
likely to reduce toxicity but could compromise effectiveness. The GDG felt that
establishing the evidence base for reducing chemotherapy cycles should be investigated in
order to quantify any risk-benefit assessment.
Clinical question: For women with stage I ovarian cancer, what is the most
effective first line chemotherapy?
Clinical evidence
The evidence for this topic consisted of one high quality Cochrane review and a lower
quality randomised controlled trial (RCT) (Table 4.2). Across these studies, women had
undergone primary surgery and had stage I or II ovarian cancer.
Winter-Roach et al., (2009) conducted a review which investigated whether adjuvant
therapy with mainly platinum-containing regimens was associated with a survival
advantage compared to withholding chemotherapy until disease progression, and whether
certain sub-groups of patients gained more or less from this approach. After an average
follow-up of nearly ten years it was found that women receiving adjuvant therapy had a
considerable advantage in overall survival (HR=0.71 [95%CI: 0.53 to 0.93] P=0.015) and
progression-free survival (HR=0.67 [95%CI: 0.53-0.84] P=0.00046). In particular, those
women who had been adequately staged gained no survival advantage from immediate
adjuvant chemotherapy (HR=1.22 [95%CI: 0.63-2.37] P=0.56) whereas women who had
been inadequately staged did (HR=0.63 [95%CI: 0.46 to 0.85] P=0.0031).
Bell et al., (2006) compared six vs. three cycles of adjuvant carboplatin and paclitaxel in
women with early stage ovarian cancer (N=457). Across all patients and after an average
follow-up of 6.8 years, there were no statistically significant differences in the risk of death
(HR=1.02 [95%CI: 0.66-1.57] P=0.94) or the rate of disease recurrence (HR=0.76 [95%CI:
0.51-1.13] P=0.18). The higher number of treatment cycles was associated with
significantly increased morbidity.
The systematic review (Winter-Roach et al., 2009) included evidence from the Adjuvant
Chemotherapy in Ovarian Neoplasm (ACTION) trial which has now been updated by
Trimbos et al., (2010). The results showed that, even with observation, optimally surgically
staged patients had a significantly better prognosis compared with patients who had been
non-optimally staged: cancer-specific survival (risk of death: HR 3.28 [95%CI: 1.47-7.33]
(P=0.002); recurrence-free survival (risk of death: HR 1.91 [95%CI: 1.17-3.11] P=0.009). In
non-optimally staged patients only, adjuvant chemotherapy provided significantly
improved cancer-specific survival (risk of death: HR 0.58 [95%CI: 0.35-0.95] P=0.029) and
recurrence-free survival (risk of death: HR 0.60 [95%CI: 0.41-0.87] P=0.007) when
compared with observation. The authors concluded, therefore, that the benefit of adjuvant
chemotherapy appeared to be limited to patients with non-optimal staging who, perhaps,
had a greater risk of unidentified residual disease.
The results of Bell et al., 2006 were re-analysed in a more recent report (Chan et al., 2010)
after a median follow-up of 91 months. The authors grouped data by tumour type (i.e.
serous or non-serous) and showed that only women with serous cancer derived a
significant benefit from six cycles compared with three cycles of adjuvant carboplatin and
paclitaxel chemotherapy (HR=0.33 [95%CI: 0.14-0.77] P=0.007). Although interesting, the
original study was underpowered for sub-group analyses which, in any event, have been
performed post hoc.
47
48
Design
Limitations
Inconsistency
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
Indirectness
no serious
imprecision
Imprecision
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
serious
imprecision1
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
randomised
trials
no serious
limitations
N/A
no serious
indirectness
N/A
no serious
imprecision
randomised
trials
no serious
limitations
N/A
no serious
indirectness
randomised
trials
no serious
limitations
N/A
no serious
indirectness
OS 10 years (sub-grouped by risk - high risk). Follow-up 46-110 months. Winter-Roach et al (2009)
N/A
N/A
OS 10 years (sub-grouped by risk - low/medium risk). Follow-up 46-110 months. Winter-Roach et al (2009)
OS 10 years (sub-grouped by risk - all). Follow-up 46-110 months. Winter-Roach et al (2009)
OS 5 years (sub-grouped by staging - sub-optimal staging. Follow-up 46-110 months. Winter-Roach et al (2009)
OS 5 years (sub-grouped by staging - optimal staging). Follow-up 46-110 months. Winter-Roach et al (2009)
OS 5 years (sub-grouped by staging - all data). Follow-up 46-110 months. Winter-Roach et al (2009)
OS 5 years. Follow-up 46-110 months. Winter-Roach et al (2009)
No of
studies
Quality assessment
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Other
389
117
506
506
Chemotherapy
383
117
500
502
Observation
No of patients
Table 4.2 GRADE profile: For women with stage I ovarian cancer, what is the most effective first line chemotherapy
not estimable
not estimable
totals not
selected
HR 0.63
(0.46 to 0.85)
P=0.0031
HR 1.22
(0.63 to 2.37)
P= 0.56
HR 0.72
(0.53 to 0.97)
P=0.033
HR 0.71
(0.53 to 0.93)
P=0.015
Relative
(95% CI)
Absolute
Summary of findings
Effect
N/A
N/A
N/A
HIGH
MODERATE
HIGH
HIGH
Quality
Design
Limitations
Inconsistency
Quality assessment
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
Indirectness
no serious
imprecision
Imprecision
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
serious
imprecision2
N/A
N/A
N/A
Other
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
randomised
trial
no serious
limitations
N/A
no serious
indirectness
N/A
no serious
imprecision
randomised
trial
no serious
limitations
N/A
no serious
indirectness
N/A
PFS 10 years (sub-grouped by risk - low/medium risk). Follow-up 46-110 months. Winter-Roach et al (2009)
PFS 10 years (sub-grouped by risk). Follow-up 46-110 months. Winter-Roach et al (2009)
N/A
N/A
N/A
PFS 5 years (data sub-grouped by staging - sub-optimal staging). Follow-up 46-110 months. Winter-Roach et al (2009)
PFS 5 years (data sub-grouped by staging - optimal staging). Follow-up 46-110 months. Winter-Roach et al (2009)
PFS 5 years (data sub-grouped by staging - all). Follow-up 46-110 months. Winter-Roach et al (2009)
PFS 5 years. Follow-up 46-110 months. Winter-Roach et al (2009)
No of
studies
Table 4.2 (Cont.)
470
117
587
587
464
117
581
583
No of patients
ObserChemotherapy
vation
not estimable
totals not
selected
HR 0.64
(0.50 to 0.82)
P=0.00041
HR 0.67
(0.36 to 1.22)
P=0.19
HR 0.64
(0.52 to 0.78)
P=0.000012
HR 0.67
(0.53 to 0.84)
P=0.00046
Relative
(95% CI)
Absolute
Effect
Summary of findings
N/A
N/A
HIGH
MODERATE
HIGH
HIGH
Quality
49
50
Design
Limitations
Inconsistency
Quality assessment
Indirectness
randomised
trial
no serious
limitations
N/A
randomised
trial
no serious
limitations
N/A
no serious
indirectness
no serious
indirectness
randomised
trials
no serious
limitations
no serious
inconsistency
no serious
indirectness
randomised
trial
no serious
limitations
N/A
no serious
indirectness
N/A
no serious
imprecision
serious
imprecision3
randomised
trial
no serious
limitations
N/A
no serious
indirectness
N/A
randomised
trial
no serious
limitations
N/A
no serious
indirectness
randomised
trial
no serious
limitations
N/A
no serious
indirectness
10 year recurrence-free survival, all patients. Follow-up 10.1 years. Trimbos et al (2010)
N/A
N/A
10 year cancer-specific survival, non-optimally staged patients. Follow-up 10.1 years. Trimbos et al (2010)
10 year cancer-specific survival, optimally staged patients. Follow-up 10.1 years. Trimbos et al (2010)
10 year cancer-specific survival, all patients. Follow-up 10.1 years. Trimbos et al (2010)
Death from ovarian cancer. Follow-up 46-110 months. Winter-Roach et al (2009)
DSS. Follow-up 46-110 months. Winter-Roach et al (2009)
N/A
Imprecision
PFS 10 years (sub-grouped by risk - high risk). Follow-up 46-110 months. Winter-Roach et al (2009)
No of
studies
Table 4.2 (Cont.)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Other
70%
(62-76%)
80%
(71-86%)
85%
(73-92%)
82%
(75-87%)
41/346
81
62%
(54-66%)
69%
(60-77%)
89%
(79-95%)
76%
(69-82%)
54/347
81
No of patients
ObserChemotherapy
vation
HR 0.64
(0.46 to 0.89)
P=0.007
HR 0.58
(0.35 to 0.95)
P=0.029
HR 1.58
(0.61 to 4.08)
P=0.34
HR 0.73
(0.48 to 1.13)
P=0.16
RR 0.76
(0.52 to 1.11)
P=0.16
HR 0.94
(0.37 to 2.37)
P=0.90
not estimable
Relative
(95% CI)
Absolute
Effect
Summary of findings
HIGH
HIGH
HIGH
HIGH
HIGH
MODERATE
N/A
Quality
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
randomised
trial
no serious
limitations
N/A
no serious
indirectness
N/A
randomised
trial
no serious
limitations
N/A
no serious
indirectness
N/A
Design
No of
studies
Limitations
no serious
limitations
Inconsistency
Quality assessment
N/A
Indirectness
no serious
indirectness
randomised
trial
serious
limitation4
N/A
no serious
indirectness
randomised
trial
serious
limitation4
N/A
no serious
indirectness
Rate of recurrence 5 years. 6 cycles vs. 3 cycles. Follow-up 6.8 years. Bell et al (2006)
Overall death rate 5 years. 6 cycles vs. 3 cycles. Follow-up 6.8 years. Bell et al (2006)
randomised
trial
serious
imprecision6
serious
imprecision5
Imprecision
N/A
10 year cancer-specific survival, patients with grade 3 disease. Follow-up 10.1 years. Trimbos et al (2010)
10 year recurrence-free survival, non-optimally staged patients. Follow-up 10.1 years. Trimbos et al (2010)
10 year recurrence-free survival, optimally staged patients. Follow-up 10.1 years. Trimbos et al (2010)
No of
studies
Table 4.2 (Cont.)
N/A
N/A
Other
N/A
N/A
N/A
Other
66%
(51-74%)
56%
(47-64%)
72%
(59-81%)
213
213
214
214
No of patients
3
6
cycles
cycles
75%
(62-84%)
65%
(56-73%)
78%
(66-86%)
No of patients
ObserChemotherapy
vation
Absolute
HR 0.76
(0.51 to 1.13)
P=0.18
HR 1.02
(0.66 to 1.57)
P=0.94
Effect
Relative
Absolute
(95% CI)
Summary of findings
HR 0.62
(0.34-1.12)
P=0.108
HR 0.60
(0.41 to 0.87)
P=0.007
HR 0.73
(0.38-1.42)
P=0.351
Relative
(95% CI)
Effect
Summary of findings
LOW
LOW
Quality
HIGH
HIGH
HIGH
Quality
51
52
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
randomised
trial
serious
limitation4
N/A
no serious
indirectness
serious
imprecision6
randomised
trial
serious
limitation4
N/A
no serious
indirectness
serious
imprecision6
N/A
N/A
Other
78.6%
60.4%
78.7%
82.7%
No of patients
3
6
cycles
cycles
HR 0.94
(0.60 to 1.49)
P=0.806
HR 0.33
(0.14 to 0.77)
P=0.007
Effect
Relative
Absolute
(95% CI)
Summary of findings
LOW
LOW
Quality
1
The 95% confidence interval spans the line of no effect and exceeds the limits of both <0.75 x the effect size (0.92) and >1.25 x the effect size (1.53). The result suggests no significant difference
between comparators.
2
3
The 95% confidence interval spans the line of no effect and exceeds the limits of both <0.75 x the effect size (0.71) and >1.25 x the effect size (1.20). This may due to low sample number. The result
suggests no significant difference between comparators.
4
There were few details of the randomisation allocation or assessment blinding methodology given.
5
6
Rate of recurrence. 6 cycles vs. 3 cycles. Follow-up 91 months. Non-serous tumours. Chan et al. (2010)
Rate of recurrence. 6 cycles vs. 3 cycles. Follow-up 91 months. Serous tumours. Chan et al. (2010)
No of
studies
Table 4.2 (Cont.)
Recommendations
Do not offer adjuvant chemotherapy to women who have had optimal surgical
staging3 and have low-risk stage I disease (grade 1 or 2, stage Ia or 1b).
Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant
chemotherapy consisting of six cycles of carboplatin.
Discuss the possible benefits and side effects of adjuvant chemotherapy with
women who have had suboptimal surgical staging3 and appear to have stage I
disease.

Interventions that improve the likelihood of disease free survival are very important, but
that benefit needs to be weighed against the morbidity and effects on overall quality of
life. The GDG noted that there was some evidence suggesting adjuvant chemotherapy in
stage I disease could reduce the risk of relapse and death from ovarian cancer. This
evidence was limited and of varying quality on the basis of study quality assessed
according to GRADE. The GDG was aware that there was a lack of data on both the
toxicity associated with adjuvant chemotherapy and on how this affected quality of life.
In women whose risk of relapse was small the GDG felt the adverse effects and costs of
adjuvant treatment would significantly outweigh any benefit from treatment and therefore
did not recommend adjuvant chemotherapy.
The GDG was also aware that different women might place different personal
value on the short-term adverse effects of treatment as well as on the possible
long-term benefits. Therefore discussion of treatment options, as well as the
option of no treatment was important.
The GDG noted that single agent platinum-based therapy, using 6 cycles of carboplatin,
had demonstrated a survival benefit in women with early stage ovarian cancer. They
were also aware that combination therapy had been shown to be more toxic than
monotherapy and has not been evaluated in this setting. The GDG therefore decided to
recommend 6 cycles of adjuvant carboplatin for most women.
This clinical question was considered a low priority for health economic evaluation
because of the small patient numbers involved.
3
References
Bell, J., M. F. Brady, R. C. Young, J. Lage, J. L. Walker, K. Y. Look, G. S. Rose, N. M. Spirtos, and Gynaecologic Oncology Group
(2006). Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian
carcinoma: a Gynaecologic Oncology Group study. Gynaecol Oncol 102: 432-439.
Chan JK., Munro EG., Cheung MK., Husain A., Teng NN., Berek JS and Osann K (2007) Association of lymphadenectomy and
survival in stage I ovarian cancer patients. Obstetrics and Gynecology 109: 12-19.
Chan JK, Tian C, Fleming GF, Monk BJ, Herzog TJ, Kapp DS et al. (2010). The potential benefit of 6 vs. 3 cycles of chemotherapy
in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology
Group study. Gynecol Oncol 116(3): 301-306.
Kim HS, Ju W, Jee BC, Kim YB, Park NH, Song YS et al. (2010) Systematic lymphadenectomy for survival in epithelial ovarian
cancer a meta-analysis. Int J Gynecol Cancer 20(4):520-528.
Optimal surgical staging constitutes midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total
random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment [Winter Roach et al. (2009)
Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews 2009,
Issue 3: CD004706]
53
Maggioni A., Benedetti PP., Dell'Anna T., Landoni F., Lissoni A., Pellegrino A., Rossi RS., Chiari S., Campagnutta E., Greggi S.,
Angioli R., Manci N., Calcagno M., Scambia G., Fossati R., Floriani I., Torri V., Grassi R and Mangioni C (2006) Randomised study
of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer 95:
699-704
National Institute for Health and Clinical Excellence (2003) Guidance on the use of paclitaxel in the treatment of ovarian cancer.
NICE technology appraisal guidance 55. London: National Institute for Health and Clinical Excellence.
Suzuki S, Kajiyama H, Shibata K, Ino K, Nawa A, Sakakibara K, Matsuzawa K, Takeda A, Kinoshita Y, Kawai M, Nagasaka T and
Kikkawa F (2008). Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell
carcinoma patients? Ann.Oncol. 19: 1284-1287.
Trimbos B, Timmers P, Pecorelli S, Coens C, Ven K, van der Burg M et al.. (2010). Surgical staging and treatment of early ovarian
cancer: long-term analysis from a randomized trial. J Natl Cancer Inst 102(13): 982-987.
Winter-Roach BA., Kitchener HC and Dickinson HO (2009). Adjuvant (post-surgery) chemotherapy for early stage epithelial
ovarian cancer. Cochrane DB Sys Rev 2009, Issue 3. Art. No: CD004706. DOI: 10.1002/14651858.CD004706.pub3.
Yang X., Hou M., Yang K., Wang H., Peng., Cao Z and Mingrong X. (2007) Prognosis in epithelial ovarian cancer: clinical analysis
of 287 pelvic and para-aortic lymphadenectomy. Chinese-German Journal of Clinical Oncology 6 (5): 492-496.
Yokoyama Y., Sakamoto T., Sato S and Saito Y (1999). Evaluation of cytoreductive surgery with pelvic and para-aortic
lymphadenectomy and intermittent cisplatin-based combination chemotherapy for improvement of long-term survival in ovarian
cancer. Eur J Gynaecol Oncol 20: 361-366.
54
5 Management of advanced
(stage II-IV) ovarian
cancer

1. to assess the role of surgery in the treatment of women with advanced stage (II-IV)
ovarian cancer and to determine the optimal timing of surgery within the treatment
pathway
2. to determine the clinical benefits and toxicity of intraperitoneal chemotherapy given as
part of the first-line management of advanced stage (II-IV) ovarian cancer.
5.1
The value of primary surgery

Surgery can be either primary (performed for the first time, either before or after
chemotherapy) or secondary (performed after primary surgery). Secondary surgery can be
sub-classified into either being early, when performed during chemotherapy (usually
termed interval debulking surgery or IDS) or late when performed after primary
chemotherapy (also called second-look laparotomy).
Historically, surgery has been an integral part of treating ovarian cancer, and before the
advent of radiotherapy and chemotherapy, the only treatment. This historical fact accounts
for why surgery came to occupy the position it does without formal scrutiny. Surgery alone
can be curative when cancer is confined to the ovaries but this is not the case for the
majority of women with ovarian cancer. It is in this group of patients that the value of
surgery, its optimal timing and extent are currently debated.
With the advent of active chemotherapy (in particular cisplatin) and its associated survival
benefit, primary cytoreductive surgery became part of standard active treatment for
advanced ovarian cancer, even in cases when all disease could not be removed. The
rationale for early cytoreductive surgery as part of primary management was to improve
tumour chemo-sensitivity and avoid chemo-resistance (Goldie & Coleman 1979: Skipper
1974). The improvement in survival seen with the advent of platinum-based therapy has
occurred despite a disparity in surgical success rates. The beneficial effects of cytoreductive
surgery in advanced disease are only seen in conjunction with active chemotherapy and
the independent contribution of surgery in this context remains to be established.
Many studies show an association between survival and the amount of postoperative
residual disease but these studies are retrospective. Although the disease remaining at the
end of the operation is a powerful adverse prognostic factor, it cannot be assumed that this
association is one of cause and effect. Consequently, debate ensues as to whether the
benefit accrued is a function of the surgery (and surgeon) or of the biological nature of the
disease. There are studies that show an association between the type of surgeon and
surgical outcome, both in terms of achieving optimal cytoreduction rates (however defined)
and survival (Bristow et al 2002; Chen et al 1985; Eisenkop et al 1992; Junor et al 1994;
55
Junor et al 1999; Kehoe et al 1994; Woodman et al 1997). This may be because some
gynaecological oncologists achieve higher optimal cytoreductive rates than other surgeons
but it might also reflect other patient factors (for example, patients with intestinal
obstruction are more likely to present to general surgeons, require emergency surgery and
have poorer prognostic factors such as ascites and poor performance scores). It is
recognised that optimal resection rates between centres can vary considerably, ranging
from 25 75% and that gynaecological oncologists can achieve high rates of cytoreduction
in cases deemed to be unresectable by less experienced surgeons (Bristow et al 2002). This
was the rationale behind the recommendation in Improving outcomes in gynaecological
cancers (Department of Health, 1999) that surgery for ovarian cancer should be carried
out by specialised gynaecological oncologists at Cancer Centres
Two approaches have developed to optimise cytoreduction rates, namely the development
of more extensive surgery and neoadjuvant chemotherapy. In the last 10-20 years, there
has been an increasing adoption of complex upper abdominal procedures, such as
peritoneal stripping, splenectomy and distal pancreatectomy to accomplish optimal
cytoreduction with acceptable morbidity. Retrospective studies, with the attendant
problems of selection bias, have shown improved optimal cytoreduction rates and suggest
an associated survival benefit in selected patients (Aletti et al 2006; Bristow et al 1999;
Eisenhauer et al 2006; Wimberger 2007). Differences in survival rates noted between
institutions might be attributable to differences in surgery but could also be due to other
variables.
The move towards extensive surgery has been coupled with a greater stringency as to what
constitutes optimal cytoreduction; this is increasingly being defined as removal of all
macroscopic disease (Chi et al., 2006; DuBois & Harter 2006; Wimberger et al., 2007).
Such extensive surgery can be complicated and carry a significant risk of morbidity.
Furthermore, the patients medical condition might preclude extensive primary surgery.
Consequently induction or neoadjuvant chemotherapy have been used to reduce tumour
burden and facilitate surgery, possibly optimising cytoreduction and reducing morbidity.
This approach has been used in the primary management of ovarian cancer in two
situations; either as induction chemotherapy after initial primary surgery and before a
second operation (termed interval debulking surgery) or as neoadjuvant chemotherapy
prior to primary surgery. Interval debulking surgery (IDS) is usually performed after 2 to 4
cycles of chemotherapy so as to prevent the development of chemo-resistance.
A number of studies have reported optimal cytoreduction rates comparable to best results
achieved at primary surgery (Chan et al 2003; Giannopoulos et al 2006; Jacob et al 1991;
Lawton et al 1989) and that these results can be achieved with less associated morbidity.
These data, from primary surgery prior to chemotherapy, or from primary surgery after
neoadjuvant chemotherapy or after IDS, all confirm the prognostic value of post-operative
residual disease status. But fundamental questions remain: is primary surgery prior to
chemotherapy more beneficial than after neoadjuvant chemotherapy; and does primary
surgery in women with advanced ovarian cancer have a therapeutic value in terms of
overall survival, especially when all macroscopic disease cannot be removed?
Clinical question: What is the effectiveness of surgery in the primary

management of women with ovarian cancer who will receive chemotherapy?
Clinical evidence
The evidence for this topic was limited and consisted of two Cochrane systematic
reviews and two small randomised controlled trials (RCTs) which dealt with different
aspects of surgery (Table 5.1). The total number of women across studies was 1,206 and
all but stage I disease was represented. None of the studies addressed patient quality of
life.
56
Morrison et al., (2007) conducted a Cochrane review of chemotherapy versus surgery for
the initial treatment of advanced ovarian cancer. Despite an extensive search of the
literature, the authors identified only one small RCT which had randomised 85 women to
receive either one cycle of chemotherapy followed by embolisation of the ovarian artery,
debulking surgery and adjuvant chemotherapy or debulking surgery and adjuvant
chemotherapy only. There was no statistically significant difference in median overall
survival (26 months [95%CI: 19.2-32.8 months] versus 25 months [95%CI: 22.8-27.2
month]) (P>0.05)) between treatments. The chemo-embolisation arm did experience less
surgery related morbidity but no other adverse events were reported.
Tangitjamol et al., (2009) reviewed three RCTs in which women with ovarian cancer
who had undergone sub-optimal primary surgery were randomised to chemotherapy
with interval debulking surgery (IDS) or chemotherapy without IDS. There was significant
between studies heterogeneity and so the authors performed sub-group analyses. They
concluded that if women had received their primary surgery from a general surgeon, as
opposed to a gynaecological oncologist, or had received less extensive surgery, then IDS
showed a marginal survival benefit (RR=0.68 [95%CI: 0.53-0.87] P=0.003). There was
no statistically significant difference between study arms in terms of either adverse events
or quality of life.
Nicoletto et al., (1997) randomised 102 women with ovarian cancer, who had an
apparently complete clinical response to primary surgery and adjuvant chemotherapy, to
either second-look surgery or a watch and wait policy. After a mean follow-up of 70
months the authors could demonstrate no significant difference in overall survival
(HR=0.68 [95%CI: 0.28-1.64] P=0.39) even though patients with a positive second-look
surgery were subsequently treated with non cross-reactive chemotherapy. Luesley et al.,
(1988) recruited women with ovarian cancer who had received primary surgery (but
were left with residual disease) and adjuvant cisplatin, randomising them to receive
either second-look surgery followed by chemotherapy with chlorambucil or pelvic
irradiation. A third group received chemotherapy only. With an average follow-up of 46
months, there was no significant difference in median overall survival between the two
surgical groups (21 months [95%CI: 11-31 months] versus 15 months [95%CI: 11-19
months)] P=0.75)) or between the surgery plus chemotherapy group versus the
chemotherapy only group (21 months [95%CI: 11-31 months] versus 17 months [95%CI:
13-21 months] P=0.75)).
Vergote et al., (2010) reported the results from a multi-centre randomised controlled trial
for which women with stage IIIC-IV ovarian cancer were recruited from 1998 to 2006.
The study compared interval debulking surgery (three cycles of platinum-based
chemotherapy before and after surgery) versus primary surgery followed by six cycles of
platinum based chemotherapy. The groups showed significant equivalent overall survival
(HR of death: 0.98 (90%CI: 0.84-1.13) (P<0.01 for non-inferiority) but equivalence could
not be demonstrated for progression-free survival (HR 1.01 (90%CI: 0.89-1.15). There
were little comparative data reported on adverse events or quality of life. This study may
have been underpowered (only 89% of the intended numbers were recruited and went
on to treatment) which may make it difficult to confidently interpret the outcomes.
57
58
Design
Limitations
Inconsist
ency
Indirectness
Imprecision
Other
RCT
serious limitations1
N/A
no serious
indirectness
serious
imprecision2
N/A
RCT
serious limitations
N/A
no serious
indirectness
serious
imprecision2
N/A
RCT
N/A
no serious
indirectness
serious
imprecision2
N/A
33.7
RCT
N/A
no serious
indirectness
serious
imprecision2
N/A
32.4
14.2
(no 95%CI)
18.2
(95%CI: 22.827.2)
25
(95%CI: 24.939.8)
(no 95%CI)
(95%CI: 19.232.8)
26
(95%CI: 24.742.6)
Relative
(95% CI)
Absolute
Summary of findings
Effect
LOW
LOW
LOW
LOW
Quality
This was a non-English language study that had not apparently been translated by the Cochrane reviewers. Although the original study authors stated that they had randomised patients, there were no details
of randomisation or allocation and blinding of outcome assessors was not mentioned. Intention to treat (ITT) analysis was used but treatment withdrawals were no discussed.
2
The Kaplan Meier plot and tables accompanying the text of Liu et al., (2004) were not accessible and may have included more data with regard to survival. However this was a low patient number trial.
Patients: women with stage III (actually II) or IV EOC; Intervention: neoadjuvant intra-arterial chemo (1 cycle), ovarian artery embolisation then primary surgery followed by adjuvant i.v. chemo (7 cycles)
(n=42); Control: primary surgery followed by adjuvant i.v. chemo (8 cycles) (n=43).
Time in months
Chemotherapy Chemotherapy
before surgery after surgery
Overall survival ( 2= 6.48; P>0.05). Follow-up 32 months (range: 8-98 months) Liu et al., 2004 (in Morrison et al. 2007)
Median DFI (P>0.05). Follow-up 32 months (range: 8-98 months) Liu et al., 2004 (in Morrison et al. 2007)
Median OS (P>0.05). Follow-up 32 months (range: 8-98 months) Liu et al., 2004 (in Morrison et al. 2007)
Mean OS (P>0.05). Follow-up 32 months (range: 8-98 months) Liu et al., 2004 (in Morrison et al. 2007)
No of
studies
Quality assessment
Table 5.1 GRADE profile: What is the effectiveness of surgery in the primary management of women with ovarian cancer who will receive
chemotherapy?
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
Other
RCT
no serious
limitations1
no serious
inconsistency2
no serious
indirectness
no serious
imprecision
N/A
177
180
RCT
no serious
limitations1
N/A
no serious
indirectness
no serious
imprecision
RCT
no serious
limitations1
no serious
inconsistency
no serious
indirectness
serious
imprecision3
N/A
N/A
7/177
216
6/180
208
(0.42-3.56)
RR=1.23
(0.79-1.24)
RR=0.99
(0.53-0.87)
RR=0.68
Relative
(95% CI)
1 fewer per 100
Absolute
Summary of findings
Effect
MODERATE
HIGH
HIGH
Quality
The three included studies in this systematic review were described by the authors as having given sufficient details of randomisation and allocation but blinding of treatment assessors was not
described. All studies used intention to treat (ITT) analysis.
2
The original pooled data for survival from the three included studies showed significant heterogeneity (I2=58%) and the authors addressed this by stratifying data by surgical speciality, as shown in the
table.
3
The confidence interval around the estimate of effect spans 1 (the line of no effect) and the limits for appreciable harm and appreciable benefit.
Toxic reactions to chemotherapy (P=0.7). Follow-up 42-48 months. Tangjitgamol et al., 2009
Risk of death (P=0.9) (if surgery was less extensive or performed by gynaecological surgeons). Follow-up 42-48 months. Tangjitgamol et al., 2009
No interval
debulking
surgery
Patients
Interval
debulking
surgery
Risk of death (P=0.04) (if surgery was performed by general surgeons). Follow-up 42-48 months. Tangjitgamol et al., 2009
No of
studies
Table 5.1 (Cont.)
59
60
Design
Limitations
Inconsistency
Quality assessment
Indirectness
N/A
no serious
indirectness
serious
imprecision2
N/A
Other
54
HR=0.68
(0.28-1.64)
No of
studies
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
[A] 2nd look surgery

Other
then chemotherapy
RCT
very serious
limitations1
N/A
no serious
indirectness
very serious
imprecision2
N/A
N=42/53
(95%CI: 11-31 months)
21 months
N=49/56
(95%CI: 11-19
months)
15 months
N=44/57
17 months (95%CI:
13-21 months)
[B] 2nd look

[C]
surgery
Chemotherapy
then radiotherapy
Summary of findings
Patients
VERY LOW
Quality
LOW
Quality
This study did not demonstrate adequate details of randomisation, allocation, blinding of treatment assessors or intention to treat (ITT) analysis.
The comparison of Group A vs. Group C may be unsafe since, on the Kaplan Meier plot shown, the lines representing each population cross several times. The statistics (chi square and P value) from
Groups A vs. B and A vs. C are identical which may be accurate or not. The study is probably underpowered to detect a significant difference between study arms.
48
Effect
Relative
Absolute
(95% CI)
Summary of findings
This study did not demonstrate adequate details of randomisation, allocation or blinding of treatment assessors. The study used intention to treat (ITT) analyses.
The confidence interval is wide and crosses the line of no effect as well as exceeding limits for appreciable harm and appreciable benefit. This is probably due to the low patient number
RCT
Imprecision
Patients
2nd look
Watchful
surgery
waiting
Median survival (A vs. B: 2=0.11; P=0.75; A vs. C: 2=0.11; P=0.75). Follow-up 46 months (range: 21-64 months). Luesley et al., 1988
Overall survival ( 2=0.74; P=0.39). Follow-up ~70 months. Nicoletto et al., 1997
No of
studies
Table 5.1 (Cont.)
Recommendation
If performing surgery for women with ovarian cancer, whether before
chemotherapy or after neoadjuvant chemotherapy, the objective should be
complete resection of all macroscopic disease.

The GDG placed a high value on the outcomes of survival and morbidity. They noted
that the evidence, using the GRADE quality assessment tool, concerning surgery was
limited, of poor quality, contradictory and open to interpretation. Therefore the GDG
made recommendations for further research into the effectiveness of surgery.
The GDG noted that in one RCT (Rose et al., 2004), the primary surgery had been
performed by gynaecological oncologists, and interval debulking surgery conferred no
significant overall survival benefit. In the two other RCTs (Redman 1994 et al., and Van
der Burg et al., 1995) the primary operations were predominantly performed by general
surgeons or gynaecologists in various hospitals and the sub-group met-analysis interval
debulking surgery performed in this group of patients appeared to confer a survival
benefit. This might suggest a value for cytoreductive surgery when done properly but the
authors of the analysis emphasised that these results have to be interpreted with caution.
This clinical question was considered a low priority for economic analysis because
although the number of patients involved could potentially be large, there was
considerable uncertainty over the health benefits of performing surgery, due to a lack of
RCT data.
Research should be undertaken to determine the effectiveness of primary surgery for
women with advanced ovarian cancer whose tumour cannot be fully excised.
5.2
Ovarian cancer commonly involves the peritoneal surfaces of the intra-abdominal cavity
without distant metastatic spread. Efforts to directly target small volume tumour deposits
have included the use of intra-peritoneal stripping, monoclonal antibodies, radionuclides
and intraperitoneal chemotherapy. The most promising of these strategies is intraperitoneal
chemotherapy and several studies have shown a moderate improvement in disease free and
overall survival. Most of these trials are dated, being carried out in the early 1990s,
involving agents such as cisplatin and cyclophosphamide, now considered inferior to the
current agents of carboplatin with or without paclitaxel.
Two more recent trials have reignited the interest in intraperitoneal chemotherapy and
confirmed the feasibility of administering paclitaxel by this route. Both trials reported
significant immediate toxicities and further research is urgently needed.
61
Clinical question: For women with ovarian cancer, is intraperitoneal

chemotherapy effective in primary management?
Clinical evidence
The evidence for this topic comprises two high quality systematic reviews (Jaaback and
Johnson, 2006; Elit et al., 2007) and one randomised controlled trial (RCT) (Wenzel et al.,
2007) (Table 5.2). Between them, these studies reported on all the outcomes of interest.
The two systematic reviews included meta-analyses of data from the same RCTs but both
reviews were appraised because the authors reported different survival outcomes. The
majority of trial data derived from the United States of America and all the studies
compared the use of standard intravenous chemotherapy with chemotherapy regimens
incorporating a component of intra-peritoneal drug delivery for the first line adjuvant
treatment of primary ovarian cancer.
High quality evidence from pooled data from up to eight trials suggested that
chemotherapy given directly into the peritoneal cavity as part of adjuvant treatment, may
significantly reduce the risk of death (HR: 0.80 [95%CI: 0.71-0.90] P=0.0003) and
disease recurrence (HR: 0.79 [95%CI: 0.69-0.90] P=0.0004) an effect also seen after five
years of follow-up (RR of death: 0.88 [95%CI: 0.81-0.95] P=0.002; RR of disease
progression: 0.91 [95%CI: 0.85] P=0.02). However, incidences of pain, fever, fatigue,
hearing loss, infection and gastrointestinal and metabolic effects occurred up to eight
times more frequently in women receiving intra-peritoneal chemotherapy. The one
exception to this observation was the incidence of cardiovascular effects which were not
significantly different between study arms. The evidence about haematological,
pulmonary, renal and neurological adverse effects was too poor in quality to allow
conclusions to be drawn about the relative contribution of the drug delivery route.
Health-related quality of life was measured in one trial and found to be significantly
worse for women receiving intra-peritoneal chemotherapy in the early days of treatment
and shortly (3 to 6 weeks) after all study treatment, but a difference between study arms
was not apparent after one year of follow-up.
62
Design
Limitations
Inconsistency
Indirectness
Imprecision
Other
serious2,3
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
895
HR 0.80
(0.71 to 0.9)
P=0.000333
Relative
(95% CI)
randomised
trials
no serious
limitations2,4
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
808
randomised
trials
no serious
limitations2,5
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
519
526
833
P=0.00044
(0.69 to 0.9)
HR 0.79
HR 0.79
(0.7 to 0.89)
P=0.00021
randomised
trials
no serious
limitations2,6
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
486
randomised
trials
no serious
limitations7
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
439/851
(51.6%)
531/886
(59.9%)
491
HR 0.78
RR 0.88
(0.81 to 0.95)
P=0.002
P=0.00025
(0.68 to 0.89)
randomised
trials
no serious
limitations6
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
352/496
(71%)
384/494
(77.7%)
P=0.02
(0.85 to 0.98)
RR 0.91
Progression-free survival (risk of progression) at 5 years (follow-up 46 to 74 months1). Effect size <1 favours intraperitoneal chemotherapy. Elit et al. (2007).
Survival (risk of death) 5 years (follow-up 46 to 74 months ). Effect size <1 favours intraperitoneal chemotherapy. Elit et al. (2007).
Time to recurrence (high quality studies only) (follow-up 46 to 74 months ). Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Time to recurrence (follow-up 46 to 74 months1). Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
7 fewer per 100

(from 16 fewer to
117 fewer)
7 fewer per 100

(from 30 fewer to
114 fewer)
Absolute
Summary of findings
Effect
Time to death (high quality studies only) (follow-up 46 to 74 months1). Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
randomised
trials
924
No of patients
IP
IV
chemochemotherapy
therapy
Time to death (follow-up 46 to 74 months1). Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
No of
studies
Quality assessment
Table 5.2 GRADE profile: For women with ovarian cancer, is intra-peritoneal chemotherapy effective in primary management
HIGH
HIGH
HIGH
HIGH
HIGH
MODERATE
Quality
63
64
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
randomised
trials
serious7
no serious
inconsistency
no serious
indirectness
serious20
N/A
Other
serious3
very serious13,14
no serious
indirectness
serious20
randomised
trials
serious3
very serious13,15
no serious
indirectness
no serious
imprecision19
serious5
serious13,16
no serious
indirectness
no serious
imprecision19
randomised
trials
no serious
limitations9
serious13,17
no serious
indirectness
no serious
imprecision19
N/A
N/A
N/A
N/A
randomised
trials
no serious
limitations9
no serious
inconsistency
no serious
indirectness
no serious
imprecision19
N/A
Adverse effects cardiovascular. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects pulmonary. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
randomised
trials
Adverse effects renal. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects leukopenia. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
randomised
trials
Adverse effects thrombocytopenia. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects anaemia. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
No of
studies
Table 5.2 (Cont.)
27/440
(6.1%)
10/455
(2.2%)
22/518
(4.2%)
477/867
(55%)
169/867
(19.5%)
79/383
(20.6%)
1 fewer per 100

(from 6 more to
1548 more)
Absolute
RR 2.55
(0.8 to 8.1)
P=0.11
RR 0.94
(0.75 to 1.19)
P=0.63
2 more per 100

(from 0 fewer to 11
more)
3 fewer per 100

(from 13 fewer to
10 more)
1 more per 100

RR 1.16
(0.33 to 4.06) (from 5 fewer to 22
more)
P=0.81
RR 0.97
(74 to 1.26)
P=0.80
Relative
(95% CI)
Summary of findings
Effect
16/437
(3.7%)
RR 1.69
(0.93 to 3.09)
P=0.085
3 more per 100

(from 0 fewer to 8
more)
RR 2.9
2 more per 100
6/486 (1.2%) (0.49 to 17.36) (from 1 fewer to 20
P=0.24
more)
8/527 (1.5%)
482/912
(52.9%)
65/912
(1.1%)
91/429
(21.2%)
No of patients
IP
IV
chemochemotherapy
therapy
HIGH
MODERATE
LOW
VERY LOW
VERY LOW
LOW
Quality
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
randomised
trials
no serious
limitations10
no serious
inconsistency
no serious
indirectness
no serious
imprecision
randomised
trials
no serious
limitations9
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
N/A
Other
serious5
serious17
no serious
indirectness
no serious
imprecision
randomised
trials
no serious
limitations9
no serious
inconsistency
no serious
indirectness
no serious
imprecision
andomized
trials
no serious
limitations9
no serious
inconsistency
no serious
indirectness
no serious
imprecision
andomized
trials
no serious
limitations11
serious13,18
no serious
indirectness
serious20
Adverse effects neurological. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects metabolic. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects infection. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
randomised
trials
N/A
N/A
N/A
N/A
Adverse effects gastrointestinal. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects fatigue. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects fever. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
No of
studies
Table 5.2 (Cont.)
108/768
(14.1%)
78/440
(17.7%)
44/440
(10%)
202/518
(39%)
43/440
(9.8%)
47/736
(6.4%)
99/803
(12.3%)
18/227
(7.9%)
16/437
(3.7%)
117/527
(22.2%)
12/437
(2.7%)
26/767
(3.4%)
No of patients
IP
IV
chemochemotherapy
therapy
3 more per 100

(from 1 more to 7
more)
Absolute
27 more per 100

(from 13 more to
49 more)
7 more per 100

(from 2 more to 14
more)
RR 1.18
2 more per 100
(0.66 to 2.05) (from 4 fewer to 13
P=0.58
more)
RR 4.38
(2.68 to 7.15)
P<0.00001
RR 2.78
(1.6 to 4.82)
P=0.00029
RR 1.60
13 more per 100
(1.13 to 2.25) (from 3 more to 28
P=0.0079
more)
RR 3.63 (1.95 to 7 more per 100

6.74)
(from 3 more to 16
P=0.00046
more)
RR 1.92
(1.2 to 3.06)
P=0.0063
Relative
(95% CI)
Summary of findings
Effect
LOW
HIGH
HIGH
LOW
HIGH
HIGH
Quality
65
66
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
randomised
trials
no serious
limitations9
no serious
inconsistency
no serious
indirectness
no serious
imprecision
randomised
trials
no serious
limitations12
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
36/487
(7.4%)
68/455
(14.9%)
59/522
(11.3%)
9/486 (1.9%)
No of patients
IP
IV
chemochemotherapy
therapy
RR 0.67
(0.46 to 0.99)
P=0.044
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
198
201
P=0.018
MD 3.6 higher
(0.61 to 6.59
higher)21
4 fewer per 100

(from 0 fewer to 6
fewer)
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
198
201
MD 1.8 higher
(0.43 to 2.97
higher)21
P=0.007
randomised trial
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
148
172
MD 6.6 higher
(4.95 to 11.45
higher)
P<0.001
QOL before cycle 4 (FACT-G) (FACT-O measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
randomised trial
QOL at baseline (FACT-O subscale) (FACT-O measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
randomised trial
Absolute
RR 8.13
13 more per 100
(4.11 to 16.1) (from 6 more to 28
P<0.00001
more)
Relative
(95% CI)
Summary of findings
Effect
QOL at baseline (FACT-G) (FACT-O measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
N/A
Other
Adverse effects hearing loss. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
Adverse effects pain. Effect size <1 favours intraperitoneal chemotherapy. Jaaback and Johnson (2006).
No of
studies
Table 5.2 (Cont.)
HIGH
HIGH
HIGH
HIGH
HIGH
Quality
Design
Limitations
Inconsistency
Quality assessment
Indirectness
Imprecision
Other
No of patients
IP
IV
chemochemotherapy
therapy
Relative
(95% CI)
Absolute
Summary of findings
Effect
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
148
172
MD 2.9 higher
(2.27 to 4.73
higher)
P<0.001
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
159
171
MD 4.6 higher
(2.89 to 9.51
higher)
P=0.002
randomised trial
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
159
171
MD 1.3 higher
(0.4 to 2.1 higher)
P=0.041
randomised trial
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
139
140
MD 0.3 higher
(1.47 lower to 5.47
higher) P=0.85
randomised trial
no serious
limitations
no serious
inconsistency
no serious
indirectness
no serious
imprecision
N/A
139
140
MD 0.2 higher
(1.15 lower to 1.55
higher) P=0.71
HIGH
HIGH
HIGH
HIGH
HIGH
Quality
7/8 trials reported duration of follow-up which in 3 trials was stated to be >60 months.
The review authors reported and assessed the allocation method, concealment, assessor blinding and intention-to-treat for all studies. On this basis they judged 3 studies to be 'good', 2 studies as fair
and 3 studies as poor in quality. Details of loss to follow-up are not reported for individual studies or overall.
3
For this outcome, 3 papers have been graded 'good', 2 as 'fair' and 2 as 'poor'.
QOL 1 year after treatment (FACT-O subscale) (measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
QOL 1 year after treatment (FACT-G) (measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
QOL 3-6 weeks after treatment (FACT-O subscale) (FACT-O measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
randomised trial
QOL 3-6 weeks after treatment (FACT-G) (FACT-O measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
randomised trial
QOL before cycle 4 (FACT-O subscale) (FACT-O measured from 0 to 156 units. Higher values indicate better QOL). MD compares IV to IP chemotherapy. Wenzel et al. (2007).
No of
studies
Table 5.2 (Cont.)
67
For this outcome, 3 papers have been graded 'good' and 2 as 'fair'.
6
7
For this outcome, 1 paper has been graded 'good', 2 as 'fair' and 1 as 'poor'.
8
9
For this outcome, 2 papers have been graded 'good'.
10
11
12
For this outcome, 2 papers have been graded 'good' and 1 as poor.
13
High levels of between studies heterogeneity in adverse effects outcomes are explained adequately in the review discussion highlighting the fact that different drugs, doses and regimes were used
across studies. Also, 2/8 of the studies used extremely high doses of chemotherapy in the intraperitoneal chemotherapy which increased the likelihood of adverse events. The authors conclude that for
leukopenia, thrombocytopenia, renal, neurological and pulmonary outcomes, data pooling (although undertaken) could be considered inappropriate.
14
Between studies heterogeneity was measured at 90%.
15
16
17
18
19
The 95% confidence interval crosses the line of no effect plus the lower value of the interval is <0.75 and/or upper value >1.25. But the event rate is <5% so study quality is not downgraded.
20
The 95% confidence interval crosses the line of no effect plus the lower value of the interval is <0.75 and/or upper value >1.25. But the event rate is >5% so study quality is downgraded
21
Calculated as a raw difference for data before randomisation and adjusted mean difference for all time points thereafter. NB. FACT-O score = scores of FACT-O subscale & FACT-G combined.
68
Recommendation
Do not offer intraperitoneal chemotherapy to women with ovarian cancer
except as part of a clinical trial.

The GDG placed a high value on improving the outcomes of disease-free and overall
survival, both of which were shown to benefit from the use of intra-peritoneal
chemotherapy compared to standard intravenous chemotherapy.
However, the GDG recognised that intra-peritoneal chemotherapy was associated with
more toxicity/adverse events than standard intravenous chemotherapy and that one study
had shown health-related quality of life to be adversely affected by intra-peritoneal
chemotherapy in the short term. The GDG also recognised that the administration of
intra-peritoneal chemotherapy was more complex and more expensive than that for
standard intravenous chemotherapy.
Although there was high-quality evidence (assessed according to GRADE analysis) on the
use of intra-peritoneal chemotherapy, the GDG noted that the studies investigated
historical drug regimens and did not investigate intra-peritoneal administration of drugs
given intravenously in current standard UK regimens. There was also a lot of
heterogeneity in the studies making it difficult to draw robust conclusions from the
evidence. In addition, only one study presented quality of life data and so it was difficult
to know if these data were representative. Based on this the GDG did not feel able to
recommend the use of intra-peritoneal chemotherapy outside of clinical trials.
This clinical question was not considered to be a high priority for health economic
evaluation due to a relatively small patient group and a lack of evidence related to
current chemotherapy agents.
5.3
Chemotherapy regimens
Recommendations on first-line chemotherapy for ovarian cancer can be found in
Guidance on the use of paclitaxel in the treatment of ovarian cancer, NICE technology
appraisal guidance 551. The recommendations which relate to first-line treatment are 1.1
and 1.2.
These recommendations refer to both early and advanced disease and should be read in
conjunction with chapter 4.
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71
6 Support needs of women

with newly diagnosed
ovarian cancer
Previous guidance on Improving outcomes in gynaecological cancers (Department of

Health, 1999) made recommendations on a number of patient perspectives related to
gynaecological cancer. These included the need for effective communication, delivery of
relevant and timely information, and psychosocial and psychosexual support and
counselling.
In addition NICE service guidance Improving palliative and supportive care for adults with
cancer (NICE, 2004) has set standards to ensure that patients with cancer, along with their
families and carers, receive the support and care to help them cope with cancer and its
treatment at all stages.
Healthcare professionals involved in the care of women with ovarian cancer are expected
to implement the recommendations made in Improving outcomes in gynaecological
cancers (Department of Health, 1999) and Improving supportive and palliative care for
adults with cancer (NICE, 2004). Implementation of these recommendations is monitored
by the National Cancer Peer Review Programme in England. This programme involves self
assessment by MDTs and external reviews of teams conducted by professional peers
against nationally agreed peer review measures1. In Wales there is a similar process of self
assessment against national minimum standards for gynaecological cancers2.
This section of the guideline specifically focuses on the support needs of women newly
diagnosed with ovarian cancer, and the psychosocial and psychosexual issues that are
particular to them.
Women diagnosed with ovarian cancer have a range of information and support needs,
whose types and timing are as varied as the people reporting them. These needs tend to be
connected with treatment, its side effects, the disease and its prognosis, as well as issues
regarding sexuality.
The Department of Health guidance Improving outcomes in gynaecological cancers
(Department of Health, 1999) included recommendations about psychosocial support and
psychosexual counselling and stated that psychosocial support should be available at
every stage to help patients and their families to cope with the effects of the disease and its
treatment. In addition, specialist interventions should be available for women and their
partners to help them to understand and cope with the effects of treatment on sexual
relationships. The guidance recommends that each patient should have access to a named
oncology clinical nurse specialist with counselling expertise.
72
http://www.cquins.nhs.uk/?menu=resources
http://wales.gov.uk/topics/health/publications/health/guidance/nationalstandardscancer?lang=en
Clinical question: For women newly diagnosed with ovarian cancer, what
support should be offered?
Clinical evidence
Evidence from qualitative studies suggests that most women with ovarian cancer need
emotional support. Improving outcomes in gynaecological cancers (Department of
Health, 1999), made a series of recommendations to improve supportive care in this
group. However, there is evidence from the Pathfinder study (Target Ovarian Cancer,
2009) that emotional support needs still go unmet in a minority of patients.
Clinical nurse specialists play an important role in emotional support for women with
ovarian cancer (Jefferies, 2002; Target Ovarian Cancer, 2009), but there is evidence that
there is variation in the workloads of nurse specialists and the resources available to them
(Target Ovarian Cancer, 2009). In the Pathfinder study only 55% of the women who
responded were given contact details for a clinical nurse specialist at the time of
diagnosis. Over a third of the women who responded (36%) were not given any contact
details at all and 25% of women who responded stated that support needs go unmet.
Most women who responded (84%) had access to a clinical nurse specialist at some
point during their cancer journey.
Women reported a range of information and support needs, reflecting different values,
preferences and circumstances. However certain types of information and support needs
were more commonly reported than others. Women were most likely to report
information and support needs connected with their treatment and its side effects and
their disease and prognosis (Beesley et al., 2008; Browall et al., 2004; Steele and Fitch
2008; Fitch and Steele, 2010).
Power et al., (2008) reported that many patients expressed a desire not to find out all the
information they could about their condition, and they purposefully avoided dealing with
it whenever possible as a coping strategy.
Recommendations
Offer all women with newly diagnosed ovarian cancer information about their
disease, including psychosocial and psychosexual issues, that:
Ensure that information is available about:
the stage of the disease, treatment options and prognosis
how to manage the side effects of both the disease and its treatments in
order to maximise well being
sexuality and sexual activity
fertility and hormone treatment
symptoms and signs of disease recurrence
genetics, including the chances of family members developing ovarian
cancer
self-help strategies to optimise independence and coping
where to go for support, including support groups
how to deal with emotions such as sadness, depression, anxiety and a
feeling of a lack of control over the outcome of the disease and treatment.
73

The GDG placed a high value on patient support but recognised there were continuing
variation and gaps in service support and delivery. The GDG felt this variation led to
unmet needs which need to be overcome.
There was good quality evidence highlighting the need for the relevant information,
tailored to the needs of the individual women, to be offered to women at the time that
most suits their individual practical and psychological needs. The GDG noted that
immediately after diagnosis, a womans most pressing information needs related to
treatment, its side effects, the disease and her prognosis. Other information including
psychosocial and psychosexual issues, although important was not ranked as highly at
this time. The GDG therefore felt it was important to make recommendations on both of
these areas.
This clinical question was not considered amenable to health economic evaluation as
there was no comparative analysis.
References
Beesley V, Eakin E, Steginga S, Aitken J, Dunn J and Battistutta D. (2008) Unmet needs of gynaecological cancer survivors:
implications for developing community support services. Psycho-Oncology 17(4): 392-400
Browall M, Carlsson M and Horvath GG. (2004) Information needs of women with recently diagnosed ovarian cancer--a
longitudinal study. Eur J Oncol Nursing 8(3): 200-7
Department of Health (1999) Improving outcomes in gynaecological cancers. Service guidance. Available from
www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4005385
Fitch M and Steele R (2010). Identifying supportive care needs of women with ovarian cancer. Canadian Oncology Nursing
Journal, 20, 66-74.
Jefferies H. (2002) Ovarian cancer patients: are their informational and emotional needs being met? J Clin Nursing 11(1): 41-7
National Institute for Clinical Excellence (2004) Improving supportive and palliative care for adults with cancer. NICE cancer
service guidance. London: National Institute for Clinical Excellence
Power J, Brown L and Ritvo P. (2008) A qualitative study examining psychosocial distress, coping, and social support across the
stages and phases of epithelial ovarian cancer. Health Care for Women International 29(4): 366-83
Steele R and Fitch MI. (2008) Supportive care needs of women with gynecologic cancer. Cancer Nursing 31(4): 284-91
Target Ovarian Cancer. (2009) Mapping the experiences of those living or working with ovarian cancer in the UK. The Target
Ovarian Cancer Pathfinder Study.
74
Appendix 1
A cost-utility analysis of diagnostic investigations in primary
care for women with symptoms of ovarian cancer
Introduction
Around 6,700 new cases of ovarian cancer are diagnosed each year in the UK (CancerResearch
UK, 2007) with an overall five-year survival of about 80% in women diagnosed with early
disease (stage I-II) and 25% in women with advanced disease (stage III-IV) (Hamilton et al.,
2009). For women presenting with symptoms in primary care, accurate diagnostic information
at this stage enables timely referral which subsequently plays a vital role in the choice of
treatment and achievable survival.
This clinical question was highlighted as a priority for economic analysis because of the large
number of patients with symptoms suggestive of ovarian cancer. In addition, there are
significant differences in costs and health outcomes associated with the different diagnostic
pathways, as well as the considerable economic burden of treating ovarian cancer.
Objective
To assess the cost-effectiveness of diagnostic strategies in primary care for women presenting
with symptoms suggestive of ovarian cancer.
Methods
Economic evaluations of a diagnostic investigation require evidence on a number of issues,
including disease prevalence and test accuracy. Furthermore, the accurate estimation of costeffectiveness of one diagnostic strategy over another requires the consideration of downstream
treatment effects, health-related preferences (utilities), healthcare resource use and unit costs.
Therefore, the evaluation was undertaken by synthesizing evidence from a number of different
sources using decision analytic techniques.
Study population
The population considered within the analysis consisted of women presenting in primary care
with symptoms consistent with suspected ovarian cancer.
Perspective
This analysis was carried out from the perspective of the UKs National Health Service (NHS), in
line with NICEs methodological recommendations. Health outcomes were expressed in terms
of quality-adjusted life-years (QALYs).
Interventions
Given the large number of different diagnostic tests and potential combinations, a decision was
made at the outset to limit the number of interventions to those that were listed by the Guideline
Development Group (GDG) in the PICO tables for this clinical question. In all, seven core
strategies were evaluated. To capture downstream consequences following the initial referral,
75
the members of the GDG were asked to identify clinical pathways that were reflective of current
UK clinical practice (Table A1.1).
Table A1.1 Summary of diagnostic strategies
Strategy Primary care diagnostic
investigation(s)
Secondary care diagnostic investigation(s)

(following referral)
Pelvic examination
Serum CA125 and ultrasound
Ultrasound*
CT scan
Serum CA125
Ultrasound
CT scan
Pelvic examination and serum CA125
Ultrasound
CT scan
Ultrasound
Pelvic examination and ultrasound
Serum CA125
CT scan
Serum CA125
CT scan
Serum CA125 and ultrasound
CT scan
Pelvic examination, serum CA125 and

ultrasound
CT scan
* Only done where pelvic examination did not detect a suspicious mass.
Structure of the model

A decision tree (Figure A1.1) was constructed outlining the seven strategies of interest: three of
the strategies included a single first test and the remaining four strategies were combination
tests. The model was constructed using TreeAge Pro (2009) software. A Markov process was
embedded in the decision tree to model recurrence of the disease and survival based on the
results of the diagnostic tests and the subsequent management of women presenting with
symptom(s) of ovarian cancer.
A hypothetical cohort of women presenting with symptom(s) of ovarian cancer in the primary
care setting was considered for the analysis. In the base case, it was considered that the starting
age of the patient population in the model was 40 years of age, while further analyses
considered a starting age of 50 years.
76
Appendix 1
Figure A1.1 Diagnostic strategies in primary care
Decision tree for accuracy of staging procedures and related complications

The square node at the beginning of the decision tree shows graphically the seven diagnostic
strategies (see Table A1.1) that have been defined as relevant to the decision problem (Figure
A1.1).
Independent of which diagnostic strategy is undertaken; patients may or may not have a
suspicious mass. This way of structuring the model allows information about the prevalence of a
suspicious mass and accuracy of the diagnostic procedures as reported in the systematic
reviews of the clinical evidence related to diagnostic investigation in primary care (in terms of
their sensitivity and specificity values (Hunink and Glasziou, 2001)) to be used.
Patients in whom the results of primary care investigation did not identify a suspicious mass
were assumed to be discharged, with the exception of those undergoing pelvic examination as
their primary care test. Patients in whom malignancy has been suspected are referred to
secondary care for further investigation. Patients who have undergone pelvic examination
(strategy 1) as part of their initial investigation in primary care are referred to secondary care if
the test outcome identifies a suspicious mass. Patients in whom pelvic examination did not
identify an abnormality undergo ultrasound in primary care. The result of the ultrasound is used
to decide whether to refer the patient to secondary care.
The pathway of diagnostic investigations in secondary care depends in part on the type of
diagnostic test performed in primary care. The diagnostic pathway for each strategy following
referral was outlined by the GDG. In order to maintain consistency within the guideline,
imaging procedures reflect the current guideline recommendations.
Pelvic examination
Patients following strategy 1 (see Table A1.1) as part of their investigation pathway and where
the initial test (pelvic examination) identified a suspicious mass, are referred to secondary care
and undergo combination serum CA125 plus ultrasound as the next diagnostic tests. At this
stage, patients in whom a suspicious mass was not detected following investigation in
77
secondary care (i.e. combination of serum CA125 plus ultrasound), undergo a repeat of the
same test within a month and are either referred for a computerised tomography (CT) scan (to
confirmed ovarian cancer) or are discharged. Patients in whom a suspicious mass was detected
undergo further investigation (in secondary care) with a CT scan, which may confirm the
presence and extent of suspected ovarian malignancy.
Serum CA125; pelvic examination plus serum CA125; ultrasound; pelvic

examination plus ultrasound
In the case of strategies 2, 3, 4 and 5 (see Table 1), those referred to secondary care with a
suspicious mass either undergo ultrasound (strategies 2 and 3) or serum CA125 (strategies 4 and
5). If the result of the ultrasound further identifies a suspicious mass, the patient undergoes a CT
scan to confirm the presence of ovarian malignancy. Similarly, patients in whom a suspicious
mass was not detected following ultrasound or serum CA125 undergo a repeat of the same test
within a month and are either referred to undergo a CT scan (to confirmed ovarian cancer) or
are discharged.
Serum CA125 plus ultrasound; pelvic examination plus CA125 plus ultrasound
Lastly, patients following strategies 6 and 7 (see Table A1.1)) where a suspicious mass was
detected, are referred to secondary care and undergo a CT scan to assess the extent of the
ovarian cancer or an alternate diagnosis.
To capture the downstream consequences of each diagnostic strategy, a clinical pathway was
outlined encompassing treatment options following confirmation of ovarian malignancy. As
such, it was agreed that following a CT scan, a proportion of patients with confirmed ovarian
malignancy, will undergo either a surgical procedure, pathological investigation (biopsy) or will
receive supportive care (where the patient is not fit for further treatment/investigation). For the
purpose of this model it was agreed that following surgical and pathological procedures patients
would be classified as either having disease confined to the ovaries (FIGO stage Ia Ic) or
disease which is not confined to the ovaries (FIGO stages II-IV). Furthermore, patients in whom
the CT scan did not confirm ovarian malignancy, undergo further investigation to differentiate
the nature of the suspicious mass. One particular issue that the model needed to deal with was
that referral and testing might correctly identify a suspicious mass that was unrelated to ovarian
cancer. It was therefore agreed that for the purposes of this model two subgroups of patients
without confirmed ovarian malignancy (but with a confirmed suspicious mass) would be
included: patients with a benign gynaecological problem (for example a simple cyst) and
patients with colorectal malignancy. Treatment options were defined for each subgroup of
patients. A summary of the key structural assumptions are listed in Box A1.1.
Box A1.1 Key Structural Assumptions
In primary care
With the exception of those undergoing pelvic examination, patients in whom no malignancy
was suspected from initial tests are discharged with no further follow up
Patients who undergo pelvic examination in primary care and have no suspicious malignancy
are re-tested using ultrasound
In secondary care
Patients in whom further investigation showed no suspicion of malignancy are re-tested within a
month
Computerised tomography scan is able to differentiate between ovarian and non-ovarian masses
Histopathological tests are assumed to be 100% accurate
78
Appendix 1
Markov process to model prognosis of patients in the long term

A Markov process was embedded in the decision tree to reflect the prognosis of patients
according to the management received following the test results. In a Markov process a patients
possible prognosis is divided into a series of discrete health states. Costs and benefits are
assigned to each health state and transition probabilities are defined to model the movement of
an individual between these health states over a particular time frame (cycle length). The costs
and benefits of comparative treatments are then estimated on the basis of the length of time
individuals spend in each health state.
The aim of introducing a Markov process at the end of the decision tree was to reflect the
pattern of recurrences and survival of patients in a simplified way, depending on whether the
diagnostic investigation had been accurate in identifying a suspected mass and, consequently,
whether patients were appropriately managed according to their true condition.
Three health states were considered for patients in whom malignancy is confined to the ovaries
and who have completed treatment: remission, recurrence and death (all causes). For patients
with advanced disease only two health states were considered: remaining in the advanced
(recurrence) disease state or death. On each given cycle, patients with confined disease could
remain in the disease-free state (remission), have a recurrence and progress to advanced disease
or die. Patients with advanced disease could either remain in the advanced stage or die.
Patients in whom colorectal malignancy was identified could either remain in that disease stage
(Dukes stage A-D), progress or die. Two health states were considered for patients who have
undergone treatment for a benign gynaecological problem, who require no further treatment or
were discharged following a negative test outcome: patients could either remain alive or die. A
one-year cycle length was used in all instances.
The different probabilities of moving from one health state to another depend on the associated
risk of recurrence, disease progression and death. Death can result from ovarian cancer (if the
patient had progressed), colorectal malignancy, or from all other causes.
Clinical evidence
Economic modelling is a useful tool to synthesise data derived from multiple sources, given the
fact that all the relevant costs and benefits of an intervention are rarely accurately captured by
one single study. Although randomised controlled trials are usually the most reliable sources of
evidence, they are not always available. Data is often used from non-randomised studies or
from expert opinion in which case transparency and consistency is essential. Conducting a
sensitivity analysis examines the robustness of the results obtained and the variables most likely
to influence the results.
Data inputs
Prevalence and test accuracy
The clinical evidence required to populate the model was obtained from the systematic reviews
conducted within the ovarian cancer guideline. The prevalence of the disease in primary care
was assumed to be a linear summation of the prevalence of ovarian and colorectal
malignancies and benign gynaecological problems. The estimates of prevalence of ovarian and
colorectal malignancies are obtained from published literature (CancerResearch UK, 2007;
Hamilton et al., 2009). GDG consensus was used to estimate the prevalence of benign
gynaecological problems. The accuracy of the diagnostic procedures, in terms of the
corresponding sensitivity and specificity values, was obtained from the systematic reviews of the
clinical evidence conducted for this guideline (see clinical evidence in sections 2.2 and 2.3).
The accuracy of combination strategies were calculated assuming conditional independence. A
summary of the estimates of disease prevalence and test accuracy used to populate the model
are reported in Table A1.2.
79
Table A1.2 Disease prevalence and test accuracy

Parameter description
Parameter estimate
Data source
Disease
Disease prevalence
Ovarian cancer
0.23%
Benign gynaecological
problem
25%
GDG consensus
Colorectal cancer
0.06%
Test accuracy
Sensitivity
Range (20% - 30%)

CancerResearchUK, 2007
Specificity
Pelvic examination
0.45
0.90
Myers et al., 2006
Serum CA125
0.78
0.78
Myers et al., 2006
Ultrasound
0.85
0.83
Liu et al., 2007
Pelvic examination + CA125
0.88
0.70
Pelvic examination +
ultrasound
0.92
0.75
Derived from single test estimates

assuming test independence (see
section 2.2 of the Evidence Review)
CA125 + ultrasound
0.97
0.65
Pelvic examination + CA125

+ ultrasound
0.98
0.58
Combination tests
Secondary care test

CT scan
0.85
0.86
Liu et al., 2007
Proportion estimates
The proportion of patients in each treatment arm, as defined by the model structure, was not
consistently reported in the published literature. Therefore, proportions were estimated by the
GDG. The estimates of the proportions are shown in Table A1.3.
Table A1.3 Estimates of proportions
Estimate (%)
Patients in whom no cancer of the ovaries was detected following secondary care test:
Proportion of patients who are diagnosed with a benign gynaecological problem (for
example a simple cyst)
85
Proportion of patient who are diagnosed with other cancer (colorectal)
15
Patients in whom cancer of the ovaries was detected following secondary care test1:
Proportion of patients undergoing percutaneous biopsy (or any other histopathological
investigation)
35
Proportion of patients undergoing surgery
60
Proportion of patients who are not fit to undergo any further investigation and receive
supportive care
1
Estimation is based on an assumption that of all patients in whom cancer of the ovaries is detected: 75% will have advanced
stage disease and 25% will have early stage disease (Kosary 1994; Bell et al., 1998). Of those with advanced stage disease 50%
will undergo surgery and 50% biopsy.
80
Appendix 1
Table A1.3 (cont.)

Estimate (%)
Patients who have undergone surgery:

Proportion of patients in whom disease is confined to the ovaries (stage I)2
40
Proportion of patients in whom disease is not confined to the ovaries (stage II-IV)
60
Patients with disease confined to the ovaries :

Proportion of patients undergoing chemotherapy (carboplatin)
50
Proportion of patients who do not require further treatment (following surgery) and
receive follow-up care
50
Patients with disease not confined to the ovaries:

Proportion of patients undergoing chemotherapy (paclitaxel/carboplatin)
85
Proportion of patients undergoing chemotherapy (paclitaxel/carboplatin) and further 10

surgery
Proportion of patients who are not fit for further treatment (following staging
surgery) and are receiving supportive care
Source: GDG Consensus; Warwick et al. 2009
Treatment
Surgery
Historically, the mainstay of treatment for ovarian cancer was surgical excision. It has been
estimated that the majority of patients with early and about half with advanced stage disease
will require some form of surgery (Bell et al., 1998; Kosary 1994). For the purpose of this model,
the GDG agreed that the majority of patients, in both groups, will undergo laparotomy with
intent to perform total abdominal hysterectomy (TAH)/bilateral salpingo-oophorectomy
(BSO)/omentectomy/peritoneal washings. In patients where no malignancy was suspected (for
example, a simple cyst) it was agreed to assume the same procedures would be carried out.
Mortality and morbidity rates associated with these surgical procedures were obtained from the
published literature (Chien et al., 2005; Gerestein et al., 2009; Loft et al., 1991; Venesmaa and
Ylikorkala 1992) or through GDG consensus and are shown Table A1.4.
Table A1.4 Mortality and morbidity associated with laparotomy
Confined to the ovaries
(stages 1a-1c)
Not confined to the

ovaries (stages II-IV)
Benign gynecological
problem
Mortality
1%
3%
0.16%
Morbidity
5%*
10-15%*
5%**
Source: Venesmaa et al., (1992); Gerestein et al., (2009) (stage II-IV); Loft et al., (1991) (benign problem); *
GDG consensus; ** Chien et al., (2005)
Chemotherapy
Within the guideline, a review of the clinical evidence was conducted to ascertain the most
effective chemotherapy regimen in patients with early disease. To assure consistency between
the guideline as a whole and the economic model, it was agreed that for the purposes of
economic analysis, patients in whom cancer is confined to the ovaries receive a carboplatinbased chemotherapy regimen. Dosage, duration of treatment, estimates of overall survival and
progression free survival were obtained from the ICON 1 trial (Swart et al., 2007)) (Table A1.5).
2
stage I includes stages Ia- Ic.
81
The study did not report major toxicities associated with carboplatin. Patients with advanced
disease (i.e. where cancer is not confined to the ovaries) followed the treatment pathway
outlined by Guidance on the use of paclitaxel in the treatment of ovarian cancer (NICE, 2003).
Similarly, estimates of overall survival, progression free survival, duration of treatment and
dosages of a combination of agents were taken from Bagnall et al., (2002) (see Table A1.5
below).
Table A1.5 Dosage, duration of treatment and survival estimates assumed by the model
Confined to the ovaries
Not confined to the ovaries
Agent (s)
Carboplatin
Paclitaxel/carboplatin
Dosage
AUC6
175 mg/m2 AUC6
Number of cycles
Progression free survival (PFS)
67% (10 years PFS)
17.1 months (median)
Overall survival (OS)
72% (10 years OS)
37.1 months (median)
Data source
ICON 1 Trial (Swart et al., 2007)
ICON 3 Trial (Bagnall et al.,

2002)
Supportive care and follow-up monitoring

Supportive care
No studies were found to provide estimates of healthcare resource use for the provision of
supportive care specifically in this group of patients. Given the advanced stage of the disease, it
was agreed that a patient will spend a third of their time at home, a third in a hospital and the
latter stage in a hospice. For the purpose of this analysis, we obtained estimates of unit costs of
resource use by GDG consensus.
Follow-up monitoring
Similarly, no studies were found quantifying healthcare resource use associated with the followup monitoring of women who had undergone treatment (surgery and chemotherapy). Other
guidelines were used to identify relevant components of care and a likely schedule of follow-up
monitoring for women who have undergone active treatment. The GDG agreed that follow-up
monitoring should include a history and physical examination (including pelvic examination)
every three months for three years and once a year for the following five years. Estimates of
resource use were obtained by GDG consensus and are summarised in Table A1.6.
Table A1.6 Resource use associated with provision of supportive care and follow-up
monitoring
Number of units
Supportive care (per patient)
Hospital stay (in days)
14
Hospice stay (in days)
14
Home stay
GP visits (0.5/week)
District nurse
Nurse specialist
Follow-up monitoring (per year)

Years 1-3
Physical examination (including pelvic examination)
Years 4 onwards
Physical examination (including pelvic examination)
82
Appendix 1
Other cancer colorectal

It was agreed that for the purposes of this economic model estimates of survival associated with
treatment for colorectal cancer would also be used as proxy for the subgroup of patients in
whom a non-gynaecological cancer was identified following diagnostic investigation. A
summary of average survival (by stage) is reported in Table A1.7.
Table A1.7 Distribution and survival by stage (at diagnosis)
Disease stage
Proportion (NCIN, 2009)
Average Survival
(Tappenden et al., 2007)
Dukes A
13.2%
11years
Dukes B
36.9%
11 years
Dukes C
35.9%
8.7 years
Dukes D
14.0%
1.4 years
Health benefits
The health benefits derived from using the alternative diagnostic strategies compared in the
analysis were estimated in terms of the number of quality-adjusted life years (QALYs) gained.
The base case analysis considered a lifetime horizon, although a shorter time horizon was
considered in the sensitivity analysis.
Markov processes were used to estimate life expectancy and QALYs gained by four different
patient subgroups:
Patients who were considered to have a suspicious mass at the beginning of the model
(following initial test) and have undergone an appropriate treatment (true positive)
Patients who did not have a suspicious mass at the beginning of the model (following
initial test) but have undergone treatment after being wrongly diagnosed (false positive)
Patients who did not have a suspicious mass at the start of the model (following initial
test) and were discharged (true negative)
Patients who have a suspicious mass at the start of the model (following initial test) but
were wrongly discharged following diagnostic investigation (false negative).
Estimates of life expectancy

Estimates of life-expectancy were generated using a series of Markov models. The transition
probabilities of moving across the various health states (Figures A1.2-A1.4) were estimated from
published studies (International Collaborative Ovarian Neoplasm Group, 2002; Swart et al.,
2007), which reported rates of remission, recurrence and death following chemotherapy
treatment in patients with localised and advanced disease. An appropriate adjustment was
conducted to obtain yearly transition probabilities of recurrence and death in this subgroup of
patients (Hunink and Glasziou, 2001). Moreover, the transition probabilities were assumed to
be constant throughout the time horizon of the model
.
83
Figure A1.2 Markov process for prognosis of patient with early ovarian disease
Figure A1.3 Markov process for prognosis of patient with advanced ovarian disease
Note: the formulae relate to the various transition probabilities and are described in more detail below (Table A1.8)
84
Appendix 1
Figure A1.4 Markov
process for prognosis of a patient with colorectal cancer
Note: the formulae relate to the various transition probabilities and are described in more detail below (Table A1.8)
For patients who did not have the disease, had a benign condition or required follow-up
monitoring after undergoing chemotherapy, transition probabilities of moving from alive to
dead from all causes were estimated using the age-related mortality rates (as reported by the
Office of National Statistics, 2009).
For patients who are diagnosed with colorectal malignancy, progression from initial stage to the
next or to death was captured by the transition probabilities reported in Tappenden et al.,
(2007).
A summary of all transition probabilities used to populate the model is reported in Table A1.8.
Table A1.8 Transition probability between health states
Transition probability
Mean
Description
tpRem_Adv
0.105
Probability of recurrence (early disease)
1-tpRem_Adv
0.895
Probability of remaining in remission
1- tpAdv_Death
0.797
Probability of remaining in the advanced disease state
tpAdv_Death
0.203
Probability of dying (advanced disease)
Ovarian cancer
85
Table A1.8 (cont.)

Mean
Description
tpCRC_A_B
0.5829
Probability of moving from Dukes A to Dukes B
tpCRC_A_Death
Probability of dying (Dukes A)
tpCRC_B_C
0.6555
Probability of moving from Dukes B to Dukes C
tpCRC_B_Death
0.01
Probability of dying (Dukes B)
tpCRC_C_D
0.8668
Probability of moving from Dukes C to Dukes D
tpCRC_C_Death
0.0602
Probability of dying (Dukes C)
tpCRC_D_Death
0.3867
Probability of dying (Dukes D)
Colorectal cancer
Utility estimates
The value of estimating the number of QALYs gained is that this single measure combines the
gains from mortality (quantity gains) and from morbidity (quality gains) (Drummond et al.,
2005). An index based on an individuals preference for a specific health state in relation to
alternative health states (utility weights) were required in the model to estimate quality-adjusted
life years (QALYs), which are calculated by weighting life expectancy by a measure of
associated health-related quality of life. Estimates of health state utilities specific to ovarian
cancer patients were obtained from published studies. There are a number of studies that report
utility weights associated with diagnostic investigations and treatments of ovarian cancer.
Havrilesky et al., (2009) reported utility estimates related to various heath states following false
positive/negative test results and treatment with toxicities. Utility estimates obtained using the
time trade-off method (TTO) tended to be slightly higher compared to those obtained using a
visual analogue score (VAS). Drummond et al., (2005) noted that visual scales for comparing
health state preferences are subject to inherent biases and are generally less accurate. For this
reason we used utility estimates derived using the TTO method. Utility estimates associated
with undergoing surgery and colorectal cancers were obtained from Grann et al., (1998) and
Tappenden, et al. (2007) respectively. The utility values used in the model are summarised in
Table A1.9.
Table A1.9 Utility values
Health state
Mean
Data Source
Diagnostic test false positive/negative result
0.88
Havrilesky et al., 2009
Chemotherapy (carboplatin)
0.81
Chemotherapy (paclitaxel)
0.55
Toxicity grade 3-4 (paclitaxel)
0.49
Surgery
0.68
Grann et al., 1998
Recurrence
0.47
Remission (early)
0.83
Stable - advanced disease
0.63
Grann et al., 1998
Colorectal cancer (by stage)
86
Dukes A
0.74
Tappenden et al., 2007
Dukes B
0.70
Dukes C
0.50
Dukes D
0.25
Supportive care
0.16
Follow-up
0.99
Assumed
Appendix 1
Cost estimates
The costs considered in this analysis were only those relevant to the UK NHS, in accordance
with the perspective taken by the NICE Reference Case for economic evaluations. Costs were
estimated based on 2008-9 prices. When costs have been taken from other sources and are
applicable to a different price year, they have been inflated using the Hospital and Community
Health Services Pay and Prices Index (PSSRU, 2009). The categories of costs included:
Cost of diagnostic tests (in primary and secondary care)
Cost of therapy (surgery, drug acquisition costs, administration costs)
Cost of major treatment related to morbidity
Cost of healthcare resource use associated with supportive care and follow-up
monitoring
Costs of diagnostic tests

The cost estimates of diagnostic tests relevant to this analysis were obtained from various
sources. Unit costs of ultrasound, CT and MRI were obtained from the NHS Reference Costs
and estimated at 69, 143 and 178 respectively (HRG codes: RA24Z, RA13Z and RA01Z).
The cost of pelvic examination was estimated using unit cost reported in the Personal Social
Services Research Unit (PSSRU 2009) and included the cost of GPs and nurses time. Unit
costs of tumour marker test (serum CA125) was estimated at 23 and obtained using GDG
consensus. Unit costs of combination tests were estimated as a sum of the unit costs of the
individual tests.
The cost estimates of pathological investigation were assumed to consist of the cost of
percutaneous biopsy and aspiration cytology. These costs were obtained from NHS Reference
costs and from GDG consensus, and were estimated to be 1,124 and 42 respectively. A
summary of unit costs of diagnostic tests are presented in Table A1.10.
Table A1.10 Cost estimates of diagnostic tests
Mean ()
Data source
69
NHS Reference Cost: HRG code RA24Z
GP practitioner (per procedure)
52
PSSRU 2009
GP nurse (per procedure)
10
PSSRU 2009
Total
62
Serum CA125
23
Ultrasound
Pelvic examination
GDG consensus
Cost estimation of combination diagnostic tests

115
85
76
Pelvic examination + ultrasound + serum

CA125
138
CT scan
143
NHS Reference Cost: HRG code RA13Z
Percutaneous biopsy
1124
NHS Reference Cost: HRG code FZ12C
Aspiration cytology
42
GDG consensus
Total
1166
MRI
178
Biopsy
NHS reference Cost: HRG code RA01Z
87
Cost of Treatment
Chemotherapy
The drug costs were calculated for chemotherapy regimens for patients with localised and
advanced disease, assuming that a patient received one dose per 3-week cycle for single or
combination therapy (Table A1.11). In addition to the drug acquisition costs, the cost of
administering the drug was estimated from the NHS Reference Costs. Administration of
carboplatin and the carboplatin/paclitaxel combination regimens was assumed to be performed
on an outpatient basis. The cost of administering these regimens was estimated using outpatient
tariffs of 272 (HRG SB12Z) and 335 (HRG SB13Z) respectively. This cost includes hospital
overheads, the administration costs of chemotherapy and clinical time. These assumptions were
verified with the GDG.
The base case analysis used list prices for drugs obtained from the British National Formulary
(BMG Group and Pharmaceutical Press, 2010). The effect of the drug discounts were explored
through sensitivity analysis.
Table A1.11 Drug acquisition costs
Strategy
Carboplatin
Carboplatin/paclitaxel
Carboplatin
Carboplatin
Paclitaxel
List prices, (BNF 59, 2010)

5 ml vial
66.85
15 ml vial
56.29
56.29
260
260
10
10
Recommended dose (mg/m )
696
660
175
Average cost per vial ()
316.29
316.29
667.88
Number of vials
Average drug cost per cycle ()
316.29
316.29
667.88
50 ml vial
601.03
60 ml vial
i.v. concentrate (mg/ml)
2
Surgery
Patients identified as having ovarian cancer or a benign gynaecological problem undergo a
surgical procedure. The unit costs considered in this analysis were estimated by mapping the
Classification of Surgical Operations and Procedures from the Office of Population, Censuses
and Survey (OPCS 4) into Health Related Groups (HRGs) and by identifying the relevant unit
cost as reported in the NHS Reference Costs for the specific HRGs. OPCS 4 codes for
laparotomy for malignant and benign conditions were obtained via GDG consensus. Costs of
surgical procedures for malignant and benign gynaecological problems are reported in Table
A1.12.
88
Appendix 1
Table A1.12 Costs of surgical procedures

Mean ()
Data source
Laparotomy with malignancy (no complications)
3,561
NHS Reference Cost: HRG code

MA06Z
Laparotomy with malignancy (with complications)
3,705

MA06Z*
Laparotomy without malignancy (no complications)
2,967

MA07B
Laparotomy without malignancy (with

3,101
complications)
MA07A
* Extra cost associated with complication was obtained using percentage change between HRG MA07A and
MA07B as a proxy.
Treatment of colorectal cancer

Lifetime costs estimates of the treatment of colorectal cancer were obtained from a published
study by Tappenden et al., (2007) and are reported in the Table A1.13 below.
Table A1.13 Lifetime costs of treatment of colorectal cancer
Disease stage
Mean cost ()
Dukes A
8,299
Dukes B
12,441
Dukes C
19,077
Dukes D
11,946
Source: Tappenden et al., 2007
Cost of supportive care and follow-up monitoring

No published data was found that quantified healthcare resource use associated with the
provision of supportive care and follow up monitoring specifically in patient subgroups
identified in the model. Categories and number of units of relevant resource use items were
obtained via GDG consensus. The total number of units for each category of resource use was
multiplied by the cost of providing it (PSSRU, 2009). A summary of unit costs for each category
of resource use are shown in Table A1.14.
Table A1.14 Unit cost of supportive care resource use
Resource
Unit cost ()
Data source
Hospital specialist palliative care support
133
NHS Reference costs: HRG code SD03A
Hospice specialist palliative care
418
NHS Reference costs: HRG code SD01A
GP visits
58
PSSRU, 2009
District nurse
114
PSSRU, 2009
Nurse specialist
82
PSSRU, 2009
Annual follow-up monitoring

Years 1-3
248
PSSRU, 2009
Year 4 (onwards)
62
PSSRU, 2009
89
Discounting
Within health economic evaluation, the discounting of costs and health outcomes is standard
practice since costs and benefits that accrue in the future are given less weight to those which
occur in the present. Following NICE methodological guidance (NICE, 2008), all costs and
health outcomes are discounted at 3.5% per year.
Sensitivity analysis
A series of one-way sensitivity analyses were conducted to assess the robustness of the study
results. One-way sensitivity analysis describes the process of changing one parameter in the
model and re-running the model to see how a change in this parameter influences overall
results.
Five scenarios were considered and are detailed below:
Nationally-agreed drug discounts in England were as follows: the cost per dose of
paclitaxel is 63.15 compared to a list price of 668 per dose (NHS Purchasing and
Supplies Agency, August 2009). The price of carboplatin is 23.93 compared to a list
price of 316 per dose. In Wales, nationally-agreed discounts were: 97% per dose for
paclitaxel and 92% for carboplatin (personal communication from the Welsh Health
Supplies, August 2009). Based on these rates, the discounted cost of each regimen was
calculated for England and for Wales. Whilst it is acknowledged that regional
pharmacies and/or commissioners may negotiate other discounts separately, only
nationally agreed discounts are considered (NICE, 2008). The average discounted cost
across both regions is also reported in Table A1.15.
The prevalence of ovarian malignancy in primary care was decreased to 0.14%.
The prevalence of benign gynaecological problem was varied over an agreed range
(20% - 30%).
The proportion of patients who are not fit for further treatment following diagnostic
investigation was decreased to 2%.
The age at the start of the model was increased from 40 to 50 years of age.
Table A1.15 Discounted drug acquisition costs in England and Wales
Regimen
Carboplatin
Carboplatin/paclitaxel
List price
316
984
Discount price (England)
26
89
Discount price (Wales)
25
45
Average cost of regimen per cycle ()
However these scenarios are unlikely to happen independently; they are more likely to occur
concurrently. To fully characterise this uncertainty and to estimate the effects of the parameter
uncertainty on the results, a probabilistic sensitivity analysis (PSA) was undertaken.
Firstly, the stochastic parameters in the model were identified (presented in the first column of
Table A1.16). These are parameters which are (arguably) measureable, but are associated with
sampling uncertainty.
Secondly, these parameters were specified as distributions rather than point estimates (see fourth
column of Table A1.16). Distributions associated with each of these parameters were selected
according to a well developed body of methodological literature. The data required to inform
these distributions was taken from the same sources as was used for the point estimates.
Parameters not chosen for PSA:
unit costs of health professionals and drug acquisition
estimates of test accuracy
90
Appendix 1
Thirdly, the analysis was run 10,000 times. For each simulation, different values were picked
from the various distributions for each stochastic parameter in the model.
Table A1.16 Parameters varied in the probabilistic sensitivity analysis
Parameter
Deterministic Distribution
value
assigned
Source
Diagnostic test false positive/negative result
0.88
Havrilesky. et al., 2009
Stable advanced disease
0.63
Beta
Grann et al., 1998
Advanced (undergoing chemotherapy)
0.55
Beta
Advanced (undergoing chemotherapy with

toxicity)
0.49
Beta
Early (chemotherapy)
0.81
Beta
Early (recurrence)
0.47
Beta
Havrilesky. et al., 2009)
Early (remission)
0.83
Beta
Surgery
0.68
Beta
Grann et al., 1998
Colorectal cancer Dukes A
0.74
Beta
Colorectal cancer Dukes B
0.70
Beta
Colorectal cancer Dukes C
0.50
Beta
Colorectal cancer Dukes D
0.25
Beta
Supportive care
0.16
Beta
Follow-up
0.99
Beta
Assumed
tpAdv_Dead
0.203
Beta
Bagnall et al., 2002
tpRem_RecAdv
0.11
Beta
Swart et al., 2007
tpCRC_A_B
0.58
Dirichlet
tpCRC_A_Death
Dirichlet
tpCRC_B_C
0.66
Dirichlet
tpCRC_B_Death
0.01
Dirichlet
tpCRC_C_D
0.87
Dirichlet
tpCRC_C_Death
0.06
Dirichlet
tpCRC_D_Death
0.39
Dirichlet
Prior disease prevalence
0.2529
Beta
Rate of toxicity (alopecia in advanced stage)
0.73
Beta
Bagnall et al., 2002
Rate of mortality (early) post surgery
0.01
Beta
Venesmaa et al. 1992
Utilities
Proportions and rates
91
Table A1.16 (Cont.)

Parameter
Deterministic Distribution
value
assigned
Source
Rate of mortality (advanced) - post surgery
0.03
Beta
Gerestein et al., 2009
Rate of mortality (benign) post surgery
0.0016
Beta
Loft et al., 1991
Rate of morbidity (early) post surgery
0.05
Beta
GDG consensus
Rate of morbidity (advanced) - post surgery
0.13
Beta
GDG consensus
Rate of morbidity (benign) post surgery
0.05
Beta
Chien et al., 1991
Proportion of patients with disease confined to

the ovaries (undergoing treatment)
0.5
Beta
GDG consensus
Proportion of patients in whom ovarian cancer (0.35; 0.60;

is detected (following secondary care test)
0.05)
Dirichlet
GDG consensus
Proportion of patients with disease not

confined to the ovaries (undergoing treatment)
(0.85; 0.1;
0.05)
Dirichlet
GDG consensus
Proportion of patients with benign

gynaecological problem
0.85
Beta
GDG consensus
Proportion of patients with colorectal cancer
0.15
Beta
GDG consensus
Proportion of Dukes A-D
(0.13; 0.37;
0.36; 0.14)
Dirichlet
Results
A summary of expected costs and effects associated with each diagnostic strategy in the model
are presented in Table A1.17. The expected cost of the strategies varies widely, ranging from the
least expensive (serum CA125) at just over 1,500 to the most expensive (combination strategy
of pelvic examination plus serum CA125 plus ultrasound) at ,3160 per patient. Health
outcomes, measured in terms of QALYs, ranged from 20.391 for the serum CA125 strategy to
19.524 for pelvic examination plus serum CA125 plus ultrasound combination strategy. Serum
CA125 (single test) strategy on average generates 20.391 QALYs and ultrasound (single test)
generates 20.387 a difference of 0.004 QALYs is an equivalent (on average) of an additional
1.5 days of perfect health.
Table A1.17 Base case total expected cost and QALYs
Cost
()
Effectiveness
(QALY)
Serum CA125
1,532.32
20.391
Ultrasound
1,604.24
20.387
(Dominated)
1,809.06
20.316
(Dominated)
1,864.16
20.298
(Dominated)
Pelvic examination
2,112.49
20.177
(Dominated)
2,850.49
19.681
(Dominated)
3,160.73
19.524
(Dominated)

CA125
ICER incremental cost-effectiveness ratio
92
ICER
Strategy
Appendix 1
All strategies in this analysis are dominated by the serum CA125 strategy. A strategy is said to be
dominated if it is both more costly and less effective than its comparator. Graphical
representation of the base case shown on Figure A1.5.
Figure A1.5 Cost-effectiveness plane for base-case results
Sensitivity analysis
The results of base case analysis were not sensitive to any of the five scenarios outlined above in
section 3.8.
The discount on paclitaxel and carboplatin available in England and Wales is considerable; the
price is about 10% of the list price. This drastically reduced the costs attributed to marginal
reduction in the overall expected costs for each of the strategies, but did not alter the ranking of
the cost-effective diagnostic strategies (Table A1.18).
Table A1.18 One-way sensitivity analysis drug discounts (the cost of paclitaxel and
carboplatin is assumed to be 89 in England and 45 in Wales instead of the base case
estimates)
Strategy
Costs ()
Costs ()
Effectiveness (QALY)
England
Wales
Serum CA125
1,525.1
1,524.8
20.3909
Ultrasound
1,596.5
1,596.2
20.3867
Pelvic examination + serum

CA125
1,800.9
1,800.5
20.3155
1,855.8
1,855.5
20.2979
Pelvic examination
2,103.8
2,103.4
20.1765
2,841.3
2,840.9
19.6802

+ serum CA125
3,151.4
3,151.0
19.5241
93
Similarly, the results of the one-way sensitivity analysis of the other scenarios (for example,
changes in the prevalence, proportion of patients undergoing supportive care and starting age of
the patients in the model) showed changes in the overall expected costs and health benefits but
did not alter the ranking of the cost-effective diagnostic strategy. The results of deterministic
sensitivity analysis are presented in Tables A1.19 and A1.20.
Table A1.19 One-way sensitivity analysis change in the (prior) prevalence of the ovarian
cancer and benign non-gynaecological cancer
Strategy
Prevalence of ovarian
cancer 0.14%
Prevalence of benign
condition 20%
Prevalence of benign
condition 30%
Costs ()
QALYs
Costs ()
QALYs
Costs ()
QALYs
Serum CA125
1,525.6
20.4024
1,362.1
20.5313
1,702.6
20.2504
Ultrasound
1,597.1
20.3989
1,423.1
20.5289
1,785.4
20.2446
serum CA125
1,801.6
20.3283
1,621.7
20.4551
1,996.5
20.1760
ultrasound
1,856.6
20.3108
1,675.8
20.4368
2,052.6
20.1590
Pelvic examination
2,104.8
20.1898
1,924.9
20.3092
2,300.1
20.0438
Serum CA125 +
ultrasound
2,843.2
19.6935
2,701.3
19.7818
2,999.7
19.5786
3,153.6
19.5374
3,023.9
19.6159
3,297.6
19.4323
ultrasound + serum
CA125
Note: setting the prevalence of colorectal cancer to 0% instead of 0.06% in a one way sensitivity analysis had a
negligible effect on the results.
Table A1.20 One-way sensitivity analysis proportions of patients receiving supportive

care estimates and starting age at time of testing
Strategy
Prop. Supportive Care

2%
Starting age
50 years
Costs ()
QALYs
Costs ()
QALYs
Serum CA125
1,532.7
20.3909
1,531.2
17.9052
Ultrasound
1,604.6
20.3868
1,603.2
17.9019
1,809.5
20.3156
1,808.0
17.8403
1,864.6
20.298
1,863.1
17.825
Pelvic examination
2,112.9
20.1766
2,111.5
17.7197
2,851.0
19.6803
2,849.7
17.2885

CA125
3,161.2
19.5242
3,160.0
17.153
To fully assess the effects of the parameter uncertainty on the results, the base case model was
estimated using probabilistic sensitivity analysis. As with the deterministic results, the results of
PSA showed serum CA125 as the dominant strategy. The corresponding cost-effectiveness
acceptability curve (CEAC) shows that, at a threshold of 20,000 per QALY, the probability that
the serum CA125 strategy is the most cost effective option is almost 73%. Moreover, the serum
CA125 strategy had the highest probability of being the most cost-effective when compared to
other strategies, at any level of willingness-to-pay per additional QALY gained (Figure A1.6).
94
Appendix 1
Figure A1.6 Cost-effectiveness acceptability curve for base case results
PE = pelvic examination; CA125 = serum CA125; USS = ultrasound
Discussion
The aim of this study was to assess the cost-effectiveness of diagnostic strategies for women
presenting with symptoms suggestive of ovarian cancer in primary care. A cost-utility analysis
was undertaken to estimate the incremental cost per QALY of seven diagnostic strategies, which
included the downstream costs and consequences of subsequent treatments considered likely to
reflect current UK clinical practice and to be consistent with recommendations made within this
guideline.
Given the various structural and parameter-related assumptions, the base-case results suggest
that serum CA125 is the most cost effective test. Indeed the results indicate that the serum
CA125 diagnostic strategy dominates all other strategies, that is, it is less costly and more
effective than at least one other option. The robustness of the model was tested using one-way
sensitivity analysis. The results of the deterministic sensitivity analysis showed that although
expected costs and health outcomes varied across strategies, the overall ranking of the costeffective strategy did not change. Moreover, probabilistic sensitivity analysis was undertaken to
fully assess the effects of the parameter uncertainty on the results. The results of the PSA showed
serum CA125 as the dominating strategy and the corresponding cost-effectiveness acceptability
curve (CEAC) shows that, at a threshold of 20,000 per QALY, the probability that the serum
CA125 strategy is the most cost effective option is almost 73%.
There are a number of limitations to this analysis. The sensitivity analyses conducted were
aimed at assessing only parameter uncertainty; however given the complexity of the
downstream consequences associated with each strategy further analysis of the later structural
assumptions would be beneficial. The costs used were often proxies for costs that were hard to
capture and may not fully capture the differences between the different diagnostic strategies, for
instance the costs of pelvic examination. Moreover, in the absence of suitable data, the
individual test results were assumed to be independent of each other, when in reality this is
unlikely. However, the implication of this in terms of the relative cost effectiveness of each of
the (combination) tests is unclear.
95
Despite these acknowledged limitations, this analysis does provide some useful information
which the guideline development group can use in its deliberations over the recommendations
to be made on this clinical question. Serum CA125 is the most cost-effective (dominating)
strategy and as shown above is more likely to be cost-effective compared to other strategies in
the model.
References
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Assessment, 1998. 2(2): 2
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Drummond M F. Sculpher MJ., Torrance GW., O'Brien BJ. and Stoddart GL. (2005). Methods for the economic evaluation of
health care programmes. Oxford: Oxford University Press, England.
Gerestein CG., Damhuis RA., Burger CW. and Kooi GS. (2009) Postoperative mortality after primary cytoreductive surgery for
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Hamilton W., Peters TJ.,, Bankhead C and Sharp D. (2009) Risk of ovarian cancer in women with symptoms in primary care:
population based case-control study. British Medical Journal. 339(7721): 616-616.
Havrilesky LJ., Broadwater G., Davis DM., et al., Determination of quality of life-related utilities for health states relevant to
ovarian cancer diagnosis and treatment. Gynecologic Oncology, 2009. 113(2): 216-220
Hunink M. and Glasziou P. (2001) Decision making in health and medicine. Cambridge University Press: Cambridge, UK.
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Kosary CL. (1994) FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of
the female gynecological system: an analysis of 1973-87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and
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Liu J., Xu Y. and Wang J. (2007) Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis of ovarian
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Loft A., Andersen TF., Brnnum-Hansen H,, Roepstorff C. and Madsen M. (1991) Early post operative mortality following
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National Cancer Intelligence Network (2009) Colorectal Cancer Survival by Stage National Cancer Intelligence Briefing. Data
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Swart AC. et al., on behalf of ICON collaborators. (2007) Long-term follow-up of women enrolled in a randomized trial of adjuvant
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96
Appendix 2
Abbreviations
AFP
alpha fetoprotein
Beta-hCG
beta human chorionic gonadotrophin
CA125
cancer antigen 125
CT
computerised tomography
FIGO
International Federation of Gynecology and

Obstetrics
GP
general practitioner
HE4
human epididymis protein 4
IBS
irritable bowel syndrome
IDS
interval debulking surgery
IP
intra-peritoneal
MDT
multidisciplinary team
MRI
magnetic resonance imaging
PET-CT
positron emission tomography fused with

computed tomography
RCT
randomised controlled trial
RMI I
risk of malignancy index I
97
Appendix 3
Glossary
Abdomen
The region of the body and its contents between the chest and the pelvis.
Adjuvant treatment
Treatment as a follow-up to surgery designed to remove any traces of tumour which may
have been left behind.
Adnexal mass
A mass in the pelvis close to one or other side of the womb.
Ascites
An abnormal accumulation of fluid in the abdominal cavity.
Benign
Something that is not cancer and treatment or removal is curative.
Bilateral lesion
Tumours that occur in both paired organs, such as the ovaries.
Bilateral salpingo-ophporectomy
Surgical removal of both fallopian tubes and ovaries.
Biopsy
Removal of a sample of tissue from the body to allow diagnosis.
Cancer Centre
Usually situated in larger hospitals, it provides a high degree of specialisation and a
comprehensive range of cancer services and treatments that encompass all facets of cancer
care necessary in modern cancer management.
Carcinoma
Cancer.
Case series
A series of case reports involving patients who were given similar treatment. Reports of
case series usually contain information about individual patients including demographic
information, information on diagnosis, treatment, response to treatment and follow-up.
Cellular product
Something produced by a cell.
98
Appendix 3
Chemotherapy
Drug(s) that kill cells dividing faster than normal. These drugs are usually used in the
treatment of cancer.
Colour Doppler ultrasound

A diagnostic imaging technique that uses ultrasound methods (sound waves) to measure the
flow of blood through a blood vessel indicated by different colours.
Computed tomography (CT)

A diagnostic imaging technique that uses X-rays and a computer to produce detailed
pictures of cross sections of the body.
Cytology
The study of cells, their origin, structure, function and pathology.
Cytoreduction
To surgically remove cancer as much as possible but perhaps not totally.
Debulking
To surgically reduce the amount cancer.
Disease free survival

Length of time after treatment during which no disease is found/seen/identified.
Disease relapse
The return of signs and symptoms of the disease after a patient has had a period of time
without any signs and symptoms.
Disease specific survival

The proportion of people in a study who have survived a particular disease since diagnosis
or treatment. Deaths from other causes are not counted.
Doppler flow
A diagnostic imaging technique that uses sound waves (ultrasound) to measure the flow of
blood through a blood vessel.
Enzyme
A protein produced by certain cells that enables biochemical reactions.
False negative
A result that appears negative but should have been positive, i.e. a test failure.
False positive
A result that appears positive but should have been negative, i.e. a test failure.
Fibrosis
An increase in fibrous tissue, e.g. scarring, which may make an area seem abnormal on
imaging or at surgery.
Frozen section diagnosis

A pathological laboratory procedure which rapidly freezes and slices tissue during surgery
for immediate microscopic analysis and diagnosis.
Gastro-splenic ligament
A structure connecting the stomach to the spleen.
99
General anaesthetic
A type of anaesthesia used for pain relief during surgical procedures, which makes you
completely lose consciousness so that the surgery can be performed without causing pain
or distress.
Grey-scale doppler
A diagnostic imaging technique that uses sound waves (ultrasound) to measure the flow of
blood through a blood vessel, indicated by proportional shades of grey.
Gynaecological oncologist
A surgeon who is an expert in the treatment of cancer affecting the female reproductive
system.
Gynaecological cancer lead

The clinician, usually a gynaecological oncologist, who leads and is responsible for the
gynaecological cancer services.
Heart failure
The inability of the heart to supply sufficient blood flow to meet the body's needs.
Heterogeneity
More variation than would be expected.
Histology or histopathology
An examination of tissue using a microscope.
Hormone
A chemical released by a cell that sends out messages that affect cells in other parts of the
body.
Hysterectomy
Surgical removal of the womb.
Imaging
The production of a clinical image using radiology, for example an x-ray, or
ultrasound/CT/MRI/PET-CT.
Image guided biopsy

A technique which uses an ultrasound or CT scanner to guide the positioning of a needle
for an accurate biopsy.
Infracolic omentectomy
Surgical excision of the pad of fat attached to the large bowel.
Interval debulking surgery

Surgery performed during primary chemotherapy with further chemotherapy to follow.
Intra-abdominal cavity
Space within the abdomen.
Intra-abdominal fluid
More fluid found in the abdomen than expected.
Chemotherapy drugs infused into the abdomen through a tube.
100
Appendix 3
Intraperitoneal stripping
Operative removal of the peritoneal lining of the abdominal cavity.
Intravenous
Infusion or injection into a vein.
Irritable bowel syndrome

A condition that affects the colon and small intestine.
Laparotomy
General term for abdominal surgery requiring an incision in the abdominal wall.
Laparoscopy
Examination of the abdominal cavity using a laparoscope (telescope).
Lesion
Term for an abnormal finding in the body.
Lesser sac
An anatomical name for the potential space in the abdomen behind the stomach.
Local anaesthetic
A type of localised anaesthesia which numbs an area of the body.
Lymphadenectomy
A surgical procedure in which lymph nodes are removed for analysis.
Lymph nodes
Small structures (glands) which act as filters of the lymphatic system. Lymph nodes close to
a primary tumour are often one of the first sites to which cancer spreads.
Lymph node assessment

This involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and
pelvic side walls wherever there is a palpable abnormality;or random sampling when this is
not the case.
Lymphocysts
A localised collection of lymph fluid from injured lymph vessels.
Lymphoedema
Distant swelling often of a limb because of obstruction or impaired circulation of lymphatic
fluid.
Magnetic resonance imaging (MRI)

A diagnostic imaging technique that uses powerful electromagnets and a computer to
produce well-defined images of the bodys internal structures.
Malignant
Cancerous.
Markers
Substances found in increased amounts in the blood, other body fluids or tissues which
may be associated with the presence of a certain type of cancer in the body
Mass
A lump.
101
Median
The middle value of an ordered set of measurements.
Menopause
The permanent cessation of ovarian function.
Meta-analysis
A method of summarising previous research by reviewing and combining the results of a
number of different clinical trials.
Metastases/Metastatic
Spread of cancer away from the original site to somewhere else in the body, usually via the
bloodstream or the lymphatic system.
Midline laparotomy
A surgical procedure involving a vertical incision through the abdominal wall to gain
access into the abdominal cavity
Monoclonal antibodies
Drugs that recognise, target, and stick to particular chemicals on the surface of cells,
stimulating the body's immune system to destroy the cells. These are artificially made in the
laboratory in pure form from a single clone of cells.
Morbidity
A diseased condition or state.
Multidisciplinary team (MDT)

A team with members from different healthcare disciplines (including for example,
oncology, pathology, radiology, nursing).
Multilocular cyst
A cyst containing internal partitions.
Multi-slice
The use of imaging techniques, such as CT or MRI scans, that can image the body in
multiple sections. These images are reconstructed by a computer.
Observational study
A non-randomised study that observes the characteristics and outcomes over time of
subjects who do and do not take a particular therapy.
Occult
Hidden or difficult to observe.
Omentum
A fold of fat attached to the stomach.
Optimal surgical staging

This comprises midline laparotomy to allow thorough assessment of the abdomen and
pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic
omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and
abdominal peritoneum and retroperitoneal lymph node assessment (Winter-Roach et al.,
2009).
Oncologist
A doctor who specialises in managing cancer.
102
Appendix 3
Organ
A structure in the body e.g. liver.
Ovary/ovaries
One or a pair of reproductive organs found in women which produce eggs and hormones.
Overall survival
The time one lives after a diagnosis of cancer. Often quoted as a percentage chance of
living a number of years (e.g. 5 or 10).
Over-expressed
An increase in the amount (and activity) of a molecule in a cell, for example of a gene or
growth factor receptor.
Para-aortic lymph node

Lymph nodes which sit in front of the lower spine either side of the aorta.
Pathology
A branch of medicine concerned with the study of disease.
Pelvis
Part of the body below the abdomen, encircled by bones.
Percutaneous core biopsy

Biopsy technique where tissue is obtained by needle puncture of a tumour through the
skin, obtaining a core of tissue for histological examination.
Peritoneum
A transparent membrane that lines the abdominal cavity.
Peritoneal deposits
Lumps of cancer that has spread to the peritoneum.
Peritoneal surfaces
Surfaces of the peritoneum lining the abdominal and pelvic cavity.
Pleural effusions
Abnormal accumulation of fluid between the lung and chest wall.
Positron emission tomography

A diagnostic imaging technique using a radio-active tracer which shows increased tissue
metabolism.
Post-menopausal
The time from one year after her last menstrual period.
Prediction model
A model which assesses the risk and susceptibility to cancer, used in clinical decision
making.
Predictive value
The chances of something happening.
Pre-menopausal
The phase in a womans life before the onset of menopause.
103
Pre-operative assessment
The assessment and management of the patient before surgery, e.g. imaging, diagnosis and
preparation for surgery.
Primary care
Services provided in a community setting, outside secondary care, where patients are
usually first seen.
Primary treatment
Initial treatment used.
Prognostic study
A study that examines selected predictive variables, or risk factors, and assesses their
influence on the outcome of a disease.
Prospective diagnostic study

A study that looks at a new diagnostic method to see if it is as good as the current gold
standard method of diagnosing a disease.
Proteins
Molecules that are made up of amino acids and are needed for the body to function
properly.
Quality of life
An overall appraisal of well being.
Radiation
Energy released in the form of particle or electromagnetic waves, which can damage living
cells.
Radiology department
A department providing a wide range of diagnostic imaging services.
Radionuclides
An unstable form of a chemical element that releases radiation as it breaks down to
become more stable.
Radiotherapy
A treatment for cancer that uses high energy ionising radiation (usually X-rays) to kill cells.
Randomised controlled trials (RCTs)

A clinical trial in which subjects are randomised to different groups for the purpose of
studying the effect of a new intervention, for example a drug or other therapy.
Receptor
A molecule inside or on the surface of a cell that binds to a specific substance, resulting in
a specific physiologic effect.
Residual disease
Cancer cells that remain after attempts to remove the cancer have been made e.g. by
surgery, chemotherapy or radiation.
Retroperitoneal
The area outside or behind the peritoneum.
104
Appendix 3
Secondary care
Services provided by the hospital, as opposed to the General Practitioner and the primary
care team.
Sensitivity
The proportion of individuals who have disease correctly identified by the study test.
Serum
The clear liquid part of the blood that remains after blood cells and clotting proteins have
been removed.
Serum tumour marker

Substances sometimes found in increased amounts in the blood, other body fluids or tissues
which suggests that a certain type of cancer may be in the body.
Spatial resolution
Ability to tell two things apart.
Specificity
The proportion of individuals who do not have a disease and who are correctly identified
by the study test.
Staging
Clinical description of the size and spread of a patients tumour, fitting into internationally
agreed categories.
Sub-diaphragmatic region
Area directly under the diaphragm.
Supportive care
Support for the patient and their family to cope with cancer and any treatment given
throughout the cancer pathway.
Systematic retroperitoneal lymphadenectomy

A systematic stripping of all lymph nodes from the pelvic and para-aortic region to the level
of the renal veins.
Systematic review
A review of the literature carried out in order to address a defined question and using
quantitative methods to summarise the results.
Tissue diagnosis
Diagnosis based on the microscopic examination of biopsies from tissues in the body.
Toxicity
Refers to the undesirable and harmful side effects of a drug.
Tuberculosis
Disease due to infection with M. tuberculosis bacteria.
Tumour marker
Substances sometimes found in increased amounts in the blood, other body fluids or tissues
which suggests that a certain type of cancer may be in the body.
105
Triage
A process in which patients are sorted according to their need for care.
Ultrasound
An imaging method in which high-frequency sound waves are used to outline a part of the
body.
Ureter
The tubes that carry urine from the kidneys to the bladder.
106
Appendix 4
Guideline scope
Guideline title
Short title
Ovarian cancer
The remit
The Department of Health has asked NICE: To prepare a clinical guideline on the
recognition and initial management of ovarian cancer, to include both surgery and
chemotherapy.'
Clinical need for the guideline

Ovarian cancer is the leading cause of gynaecological cancer death in the UK and its
incidence is rising. It is the fourth most common malignancy in women, with a lifetime risk
of about 2% in England and Wales.
The overall outcome for women with ovarian cancer is poor, with an overall 5-year
survival rate of less than 30%. This is because most women who develop ovarian cancer
present with advanced disease.
The stage of the disease is the most important factor with regard to outcome. The woman's
general health at the time of presentation is also important because it affects what
treatments can be used. Most women have had symptoms for months prior to initial
presentation, and there are often delays between initial presentation and specialist referral.
There is a need for greater awareness of the disease and also initial investigations enabling
earlier referral and maximising of treatment options.
Current practice
There are variations in:
modalities used for early detection and diagnosis of ovarian cancer
the number of drugs used and duration of treatment in women with ovarian cancer
the timing, extent and effectiveness of surgery in women with ovarian cancer in whom
complete removal of the disease is not possible.
A clinical guideline will help to address these issues and offer guidance on best practice.
The guideline
The guideline development process is described in detail on the NICE website (see Further
information).
This scope defines what the guideline will (and will not) examine, and what the guideline
developers will consider. The scope is based on the referral from the Department of Health.
107
If we are to produce a high-quality guideline within the allotted time it will not be possible
to cover the entire care pathway described by the remit.
Therefore we intend to focus on clinical issues:
for which there is uncertainty or disagreement on best practice
that will have the most significant impact on the clinical service and on the
management of patients with ovarian cancer
that could improve health outcomes and/or make better use of health resources
that could help to avoid unlawful discrimination and reduce health inequalities.
A list of the key clinical issues (section 4.4) has been developed using advice from the
Guideline Development Group chair and clinical lead, attendees at the NICE ovarian
cancer stakeholder workshop and registered stakeholders. We acknowledge that there will
be some important topics that are not part of the final prioritised list.
The areas that will be addressed by the guideline are described in the following sections.
Population
Groups that will be covered
Adult women (18 years and older) with epithelial ovarian cancer.
Adult women with fallopian tube carcinoma.
Adult women with primary peritoneal carcinoma.
Adult women with suspected ovarian or primary peritoneal carcinoma.
Adult women with borderline ovarian cancer.
No patient subgroups needing special consideration have been identified.
Groups that will not be covered
Children (younger than 18 years) with ovarian malignancy.

Women with pseudomyxoma peritonei.
Women with relapsed ovarian, fallopian tube or peritoneal cancer.
Women with germ cell tumours of the ovary.
Women with sex cord stromal tumours of the ovary.
Women with secondary cancers metastasising to the ovary or peritoneum.
Healthcare setting
Primary care.
Secondary care, including diagnosis, surgery and chemotherapy.
Tertiary care in cancer centres, and regional centres with specialties such as
intraperitoneal chemotherapy.
NHS hospice care.
Main outcomes
108
Sensitivity of diagnostic tests

Specificity of diagnostic tests
Overall survival
5 year survival
Median survival
Disease free survival
Morbidity
Mortality
Number and severity of adverse events
Quality of life
Appendix 4
Clinical management
Key clinical issues that will be covered
The signs and symptoms of ovarian cancer.

The relationship between the duration of pre-diagnostic symptoms of ovarian cancer
and survival.
For women with suspected ovarian cancer, the most effective first test in primary care.
For women with suspected ovarian cancer, the most effective malignancy index.
For women with suspected ovarian cancer, the serum tumour marker tests that should
be routinely carried out to determine future management.
For women with suspected ovarian cancer, the most appropriate imaging to be done to
determine future management.
For women with suspected ovarian cancer, when it is appropriate not to have a tissue
diagnosis before starting chemotherapy.
The best method of tissue diagnosis before chemotherapy: samples from image guided
biopsy or laparoscopic biopsy.
The effectiveness of surgery in the primary management of women with ovarian
cancer, who will receive chemotherapy.
For women with ovarian cancer whose disease appears to be confined to the ovaries,
the effectiveness of systematic retroperitoneal lymphadenectomy in surgical
management.
For women with ovarian cancer, the effectiveness of intra-peritoneal chemotherapy in
primary management.
For women diagnosed with ovarian cancer, the support that should be offered.
What is the most clinically effective primary chemotherapy for women with ovarian
cancer
Clinical issues that will not be covered
Population-based screening.
Surveillance of high-risk groups, including women with a family history of ovarian
cancer.
Economic aspects
Developers will take into account both clinical and cost effectiveness when making
recommendations involving a choice between alternative interventions. A review of the
economic evidence will be conducted and analyses will be carried out as appropriate. The
preferred unit of effectiveness is the quality-adjusted life year (QALY), and the costs
considered will usually only be from an NHS and personal social services (PSS)
perspective. Further detail on the methods can be found in The guidelines manual (see
Further information).
Status
Scope
This is the final scope.
Guideline
The development of the guideline recommendations will begin in May 2009.
109
Related NICE guidance
Referral guidelines for suspected cancer. NICE clinical guideline 27 (2005). Available
from www.nice.org.uk/CG27
Improving supportive and palliative care for adults with cancer. Cancer service
guidance (2004). Available from www.nice.org.uk/csgsp
Guidance on the use of paclitaxel in the treatment of ovarian cancer. NICE technology
appraisal guidance 55 (2003). Available from www.nice.org.uk/TA55
Improving outcomes in gynaecological cancers. Cancer service guidance (1999).
Department of Health, National Cancer Guidance Steering Group. Available from:
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPoli
cyAndGuidance/DH_4005385
Further information
Information on the guideline development process is provided in:
How NICE clinical guidelines are developed: an overview for stakeholders, the public
and the NHS
The guidelines manual.
These are available from the NICE website (www.nice.org.uk/guidelinesmanual).
Information on the progress of the guideline will also be available from the NICE
website (www. nice.org.uk).
110
Appendix 5
List of topics covered by each chapter
Chapter 2 Detection in primary care
What are the symptoms and signs of ovarian cancer?

What is the relationship between the duration of pre-diagnostic symptoms of
ovarian cancer and survival?
For women with suspected ovarian cancer, what are the most effective first tests in
primary care?
Chapter 3 Establishing the diagnosis in secondary care
For women with suspected ovarian cancer, what serum tumour marker tests
should be routinely carried out to aid in diagnosis?
For women with suspected ovarian cancer, which malignancy index is the most
effective?
For women with suspected ovarian cancer, what is the most appropriate imaging
to be done to determine future management?
For women with suspected advanced ovarian cancer, when is it appropriate not to
have a tissue diagnosis before starting chemotherapy?
What is the best method of tissue diagnosis before chemotherapy, samples from
image guided biopsy or laparoscopic biopsy?
Chapter 4 Management of suspected early stage ovarian cancer
For women with ovarian cancer whose disease appears confined to the ovaries,
what is the effectiveness of systematic retroperitoneal lymphadenectomy in
surgical management?
For women with stage I ovarian cancer, what is the most effective first line
chemotherapy?
Chapter 5 Management of advanced stage (II-IV) ovarian cancer
What is the effectiveness of surgery in the primary management of women with

ovarian cancer who will receive chemotherapy?
For women with ovarian cancer, is intra-peritoneal chemotherapy effective in
primary management?
Chapter 6 Support needs for women with newly diagnosed ovarian cancer
For women newly diagnosed with ovarian cancer, what support should be offered?
111
Appendix 6
People and organisations involved in production of the
guideline
112
6.1
Members of the Guideline Development Group
6.2
Organisations invited to comment on guideline development
6.3
Individuals carrying out literature reviews and complementary work
6.4
Members of the Guideline Review Panel
Appendix 6.1
Members of the Guideline Development Group (GDG)
GDG Chair
Mr Sean Duffy
Medical Director of the Yorkshire Cancer Network
GDG Lead Clinician

Mr Charles Redman
Consultant Gynaecological Oncologist, University

Hospital of North Staffordshire, Stoke-on-Trent
Group Members
Dr Susan Barter
Consultant Radiologist, Addenbrookes Hospital,

Cambridge University Hospitals Foundation
Audrey Bradford
Network Director, Anglia Cancer Network
Dr Laurence Brown
Consultant Histopathologist, Leicester Royal Infirmary,

Leicester
Mr Derek Cruickshank
Consultant Gynaecological Oncologist, The James Cook

University Hospital, Middlesbrough
Dr Craig Dobson
Senior Lecturer in Medical Education and General

Practice, Hull/York Medical School
Linda Facey
Patient/carer member
Dr Marcia Hall
Consultant in Medical Oncology, Mount Vernon Cancer

Centre, Middlesex
Mr Jed Hawe
Consultant Obstetrician and Gynaecologist and Local

Gynaecological Cancer Lead, Countess of Chester NHS
Foundation Trust
Dr Cathy Hughes
Clinical Nurse Specialist and Cancer Lead, National

Patient Safety Agency, London
Frances Reid
Patient/carer member, Target Ovarian Cancer
Michael Scanes
Patient/carer member
Professor Nicholas SA
Stuart
Medical Oncologist and Professor of Cancer

Studies,University of Bangor
113
Declarations of interest
The Guideline Development Group were asked to declare any possible conflicts of interest
which could interfere with their work on the guideline. The interests that were declared are
as follows:
114
GDG Member
Interest Declared
Type of Interest
Decisions Taken
Mr Sean Duffy
Non-personal
Chief investigator for a trial of a
nutritional supplement in patients with pecuniary, specific
ovarian cancer, that is receiving
support from Nutricia
Declare and can participate in

discussions on all topics as
interventions included in the
trial or made by Nutricia are
not being investigated by the
guideline
Mr Charles
Redman
Received travel and subsistence

expenses from Schering Plough
Oncology to take part in a debate on
the role of lymphadenectomy with a
group of gynae-oncologists in March
2010
Personal
pecuniary, specific

discussions on all topics as the
expenses were not beyond
reasonable amounts
Professor
Nicholas S A
Stuart
Chief investigator for a trial

investigating the mechanisms of
fatigue induced by sunitinib in
patients with advanced/metastatic
renal cancer, which received funding
from Pfizer
Non-personal
pecuniary, nonspecific

discussions on all topics as
interventions included in the
trial or made by Pfizer are not
being investigated by the
guideline

expenses from Novartis to attended
the American Society of Clinical
Oncology meeting in May 2009
Personal

reasonable amounts
Michael Scanes
Member of the group that recently

published Key Messages on Ovarian
Cancer
Personal nonpecuniary

discussions on all topics
Frances Reid
Involved in advocating for the role of

symptoms in ovarian cancer to be
acknowledged, based on research
emerging from the USA

Dr Marcia Hall

expenses from Boehringer Ingelheim
to attend the American Society of
Clinical Oncology meeting in June
2010
Personal

reasonable amounts
Mr Derek
Cruickshank
Asked to provide expert advice, by

The HTA, on the value of research
into hyperthermic intra-peritoneal
chemotherapy in ovarian cancer

Appendix 6.2
Organisations invited to comment on guideline development
The following stakeholders registered with NICE and were invited to comment on the scope and the draft
version of this guideline.
A Little Wish
British Gynaecological Cancer Society
Abbott Laboratories Limited
British National Formulary (BNF)
Aberdeen Royal Infirmary
British Nuclear Medicine Society
Airedale NHS Foundation Trust
British Society for Cancer Genetics
Almac Diagnostics
British Society for Human Genetics
Anglia Cancer Network
British Society of Urogynaecological Radiology
Arden Cancer Network
BUPA
Association for Clinical Biochemistry
Cambridge University Hospitals NHS

Foundation Trust (Addenbrookes)
Association for Palliative Medicine of Great

Britain and Ireland
Cancer Care Cymru
Association of British Insurers (ABI)
Cancer Research UK
Association of Chartered Physiotherapists in

Oncology and Palliative Care
Care Quality Commission (CQC)
Association of Clinical Biochemists, The

Association of clinical pathologists
Association of the British Pharmaceuticals
Industry (ABPI)
AstraZeneca UK Ltd
Barnsley Hospital NHS Foundation Trust
Central South Coast Cancer Network

Cheshire PCT
College of Emergency Medicine
College of Occupational Therapists
Commission for Social Care Inspection
Connecting for Health
Beckman Coulter UK Ltd
Daiichi Sankyo UK
Belfast Health and Social Care Trust
Department for Communities and Local

Government
Birmingham Cancer Network

Birmingham Womens NHS Trust
BMJ
Boehringer Ingelheim Ltd
Department of Health
Department of Health Advisory Committee on
Antimicrobial Resistance and Healthcare
Associated Infection (ARHAI)
Brighton and Sussex University Hospitals Trust
Department of Health, Social Services & Public

Safety, Northern Ireland (DHSSPSNI)
British Dietetic Association
Derby-Burton Cancer Network
115
Derbyshire Mental Health Services NHS Trust

Dorset Cancer Network
East Lancashire Hospitals NHS Trust
East Midlands Cancer Network
Essex Cancer Network
Eusapharma (Europe) Ltd
Eve Appeal, The
GE Healthcare
GlaxoSmithKline UK
Greater Manchester and Cheshire Cardiac and
Stroke Network
Greater Midlands Cancer Network
Guerbet Laboratories Ltd
Guys and St Thomas NHS Trust
Harrogate and District NHS Foundation Trust
Hospira UK Limited
Human Fertilisation and Embryology Authority
Humber and Yorkshire Coast Cancer Network
Imaging Equipment Limited
Institute of Biomedical Science
James Cook University Hospital
Leeds PCT
National Treatment Agency for Substance

Misuse
NCC - Cancer
NCC - Mental Health
NCC - National Clinical Guidance Centre
(NCGC)
NCC - Women & Children
NETSCC, Health Technology Assessment
NHS Clinical Knowledge Summaries Service
(SCHIN)
NHS Direct
NHS Improvement
NHS Kirklees
NHS Knowsley
NHS Plus
NHS Quality Improvement Scotland
NHS Sefton
NHS Sheffield
NHS Western Cheshire
NICE - CPHE
NICE - CPHE Methodology - Simon for info
NICE - Guidelines Coordinator - for info
NICE - Guidelines HE for info
Leeds Teaching Hospitals NHS Trust
NICE Implementation consultant - Region East
Leicestershire Northamptonshire and Rutland

Cancer Network
NICE - Implementation consultant - Region SW
Luton & Dunstable Hospital NHS Foundation

Trust
Lymphoedema Support Network, The
Macmillan Cancer Support
Medical Research Council Clinical Trials Unit
NICE - Implementation consultant - SE/London

NICE - Implementation consultant - Region
NW/NE
NICE - Implementation consultant - Region
West Midlands
NICE - Implementation co-ordination - for info
Medicines and Healthcare Products Regulatory

Agency (MHRA)
NICE - PPIP
Ministry of Defence (MoD)
NICE - Technical Appraisals (Interventional

Procedures) - for info
MRC-CTU
National Council for Palliative Care
National Patient Safety Agency (NPSA)
National Public Health Service for Wales
116
North East London Cancer Network

North East London Cancer Network
North Tees and Hartlepool Acute Trust
North Trent Cancer Network
Appendix 6.2
North West London Cancer Network

North Yorkshire and York PCT
Northern Ireland Cancer Network
Nottingham University Hospitals NHS Trust
Scottish Intercollegiate Guidelines Network

(SIGN)
Sedgefield PCT
Sheffield PCT
Novartis Pharmaceuticals UK Ltd
Sheffield Teaching Hospitals NHS Foundation

Trust
Novo Nordisk
Social Care Institute for Excellence (SCIE)
Ovacome
Ovarian Cancer Action
Patients Council
Pelvic Pain Support Network
PERIGON Healthcare Ltd
Pfizer Limited
Poole and Bournemouth PCT
Randox Laboratories Ltd
Society and College of Radiographers

South East Wales Cancer Network
South Tees Hospitals NHS Trust
Southend University Hospitals NHS Trust
Sussex Cancer Network
Target Ovarian Cancer
Teenage Cancer Trust, The
Roche Diagnostics
Teenagers and Young Adults with Cancer

(TYAC)
Roche Products Limited
Thames Valley Cancer Network
Royal College of General Practitioners
The Roy Castle Lung Cancer Foundation
Royal College of General Practitioners Wales
The Royal College of Radiologists
Royal College of Nursing
The Society and College of Radiographers
Royal College of Obstetricians and

Gynaecologists
UK Clinical Pharmacy Association
Royal College of Pathologists
University Hospital Birmingham NHS

Foundation Trust
Royal College of Physicians London
Welsh Assembly Government
Royal College of Radiologists
Welsh Scientific Advisory Committee (WSAC)
Royal Cornwall Hospitals Trust
West Hertfordshire PCT & East and North

Hertfordshire PCT
Royal Society of Medicine

Sandwell PCT
Sanofi-Aventis
Schering-Plough Ltd
Western Cheshire Primary Care Trust

Western Health and Social Care Trust
York NHS Foundation Trust
117
Appendix 6.3
Individuals carrying out literature reviews and complementary
work
Overall Co-ordinators
Dr John Graham
Director, National Collaborating Centre for Cancer, Cardiff
Dr Andrew Champion
Centre Manager, National Collaborating Centre for Cancer,

Cardiff
Project Managers
Angela Bennett
Assistant Centre Manager, National Collaborating Centre for

Cancer, Cardiff
Victoria Titshall1
National Collaborating Centre for Cancer, Cardiff
Helen Pearson2
Researchers
Dr Nathan Bromham
Dr Karen Francis
Senior Researcher, National Collaborating Centre for Cancer,

Cardiff
Angela Melder3
Senior Researcher, National Collaborating Centre for Cancer,

Cardiff
Dr Lakshmi Sandu Aana
Registrar in Obstetrics and Gynaecology, Northwest Deanery
Information Specialists
Elise Collins
Sabine Berendse
Stephanie Arnold4
From March 2010 August 2010
From August 2009 February 2010

From October 2008 November 2009
3
4
118
From October 2008 October 2009
Appendix 6.3
Health Economists
Eugenia Priedane
Research Assistant, London School of Hygiene and Tropical

Medicine
Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and

Tropical Medicine
Needs Assessment
Dr Lakshmi Sandu Aana
Registrar in Obstetrics and Gynaecology, Northwest Deanery
119
Appendix 6.4
Members of the Guideline Review Panel
The Guideline Review Panel is an independent panel that oversees the development of the
guideline and takes responsibility for monitoring its quality. The members of the Guideline
Review Panel were as follows:
Dr John Hyslop Chair
Consultant Radiologist, Royal Cornwall Hospital NHS Trust
Dr Ash Paul
Deputy Medical Director, Health Commission Wales
Professor Liam Smeeth
Professor of Clinical Epidemiology, London School of Hygiene and Tropical Medicine
Kieran Murphy
Health Economics & Reimbursement Manager, Johnson & Johnson Medical Devices &
Diagnostics (UK)
Sarah Fishburn
Lay member
Members of the NICE project team

Fergus Macbeth
Centre for Clinical Practice Director
Nicole Elliott1
Guideline Commissioning Manager
Claire Turner2
Guideline Commissioning Manager
Emma Banks3
Guidelines Coordinator
Anthony Gildea4
Guidelines Coordinator
1
2
3
4
120
From October 2008 July 2009

October 2009 present
From October 2008 June 2010
June 2010 present
Appendix 6.4
Amanda Killoran
Technical Lead
Stefanie Reken
Health Economist
Lynn Knott
Editor
Barbara Meredith
Patient Involvement Lead
121

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Ovarian cancer:

the recognition and initial

This guidance updates and replaces recommendation 1.7.4 in

Developed for NICE by the National Collaborating Centre for Cancer

Key research recommendations

List of all recommendations

Detection in primary care

Establishing the diagnosis in secondary care

Tumour markers: which to use?

Imaging in the diagnostic pathway: which procedures?

Management of suspected early (stage I) ovarian cancer

The role of systematic retroperitoneal lymphadenectomy

Adjuvant systemic chemotherapy for stage I disease

Management of advanced (stage II-IV) ovarian cancer

The value of primary surgery

Support needs of women with newly diagnosed ovarian cancer

Awareness of symptoms and signs

Asking the right question first tests

See Box 3.1 for details of how to calculate an RMI I score.

Ovarian cancer: the recognition and initial management of ovarian cancer

The role of systematic retroperitoneal lymphadenectomy

Adjuvant systemic chemotherapy for stage I disease

Support needs of women with newly diagnosed ovarian cancer

Ovarian cancer: the recognition and initial management of ovarian cancer

Systematic retroperitoneal lymphadenectomy is an untested procedure but is likely to be

List of all recommendations

Chapter 2: Detection in primary care

Asking the right question first tests

Ovarian cancer: the recognition and initial management of ovarian cancer

Chapter 3: Establishing the diagnosis in secondary care

Calculate a risk of malignancy index I (RMI I) score4 (after performing an ultrasound;

Imaging in the diagnostic pathway: which procedures?

If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer,

Methods of tissue diagnosis other than laparotomy

See Box 3.1 for details of how to calculate an RMI I score.

List of all recommendations

Chapter 4: Management of suspected early (stage I)

Perform retroperitoneal lymph node assessment5 as part of optimal surgical staging6 in

Adjuvant systemic chemotherapy for stage I disease

Chapter 5: Management of advanced (stage IIIV)

Do not offer intraperitoneal chemotherapy to women with ovarian cancer, except as

Chapter 6: Support needs of women with newly diagnosed

Ovarian cancer: the recognition and initial management of ovarian cancer

Ensure that information is available about:

Who is the guideline intended For?

The remit of the guideline

Ovarian cancer: the recognition and initial management of ovarian cancer

The process of guideline development who develops the

The guideline development group (GDG)

Guideline Development Group meetings

Developing Clinical Evidence-Based Questions

Ovarian cancer: the recognition and initial management of ovarian cancer

Review of Clinical Literature

Developing the review protocol

The clinical question as agreed by the GDG.

Short description; for example To estimate the effects and

Criteria for considering studies for the review

Using the PICO (population, intervention, comparison

How the information will be searched

The sources to be searched and any limits that will be

The review strategy

The methods that will be used to review the evidence,

Searching for the evidence